T cells Abul K. Abbas: Basic Immunology page 49-71 (fig3.7, 3.9, 3.11, 3.16 are not required) and 105-115 (fig 5.11, 5.18 are not required)

T cells Abul K. Abbas: Basic Immunology page (fig3.7, 3.9, 3.11, 3.16 are not required) and (fig 5.11, 5.18 are not required)

T helper cells (TH cells) assist other white blood cells in immunologic processes
Cytotoxic T cells (TC cells, or CTLs) destroy virally infected cells and tumor cells T lymphocytes consist of functionally distinct populations: helper T cells and cytotoxic (or cytolytic) T lymphocytes (CTLs). In response to antigenic stimulation, helper T cells secrete proteins called cytokines, which are responsible for many of the cellular responses of innate and adaptive immunity and thus function as the "messenger molecules" of the immune system. The cytokines secreted by helper T lymphocytes stimulate the proliferation and differentiation of the T cells themselves and activate other cells, including B cells, macrophages, and other leukocytes. CTLs kill cells that produce foreign antigens, such as cells infected by viruses and other intracellular microbes and responsible for killing tumor cells.

T cells MHCI, presentation of intracellular pathogens
MHCII, presentation of extracellular pathogens T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells

! ! II ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES ! ! T II Cell surface MHC-peptide complex T-cell response soluble Ag Peptide antigen Native membrane Ag Cell surface peptides APC T lymphocytes recognize peptide antigens that are bound to and displayed by major histocompatibility complex (MHC) molecules of antigen-presenting cells. T cell receptor recognizes a complex of peptide antigen displayed by an MHC molecule. Major histocompatibility complex (MHC) molecules are expressed on antigen-presenting cells and function to display peptides derived from protein antigens. The cells that capture microbial antigens and display them for recognition by T lymphocytes are called antigen-presenting cells (APCs). APC APC No T-cell response

Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells. Dendritic cells take up antigen in the tissues, migrate to peripheral lymphoid organs, and present foreign antigens to naive T cells. In the example illustrated, of a wound in the skin, immature dendritic cells in the skin, known as Langerhans cells, take up antigen locally and migrate to a nearby lymph node. There they settle in the T-cell areas and differentiate into mature dendritic cells. 5

Interaction of antigen presenting cell and T cell
TCR MHC peptid T lymphocytes recognize peptide antigens that are bound to and displayed by major histocompatibility complex (MHC) molecules of antigen-presenting cells. Antigens that are transported by dendritic cells to lymph nodes are recognized by naive T lymphocytes that recirculate through these lymph nodes. The naive T cells are activated to differentiate into effector and memory cells, which may remain in the lymphoid organs or migrate to nonlymphoid tissues. At sites of infection, the effector cells are again activated by antigens and perform their various functions, such as macrophage activation. APC

System optimalization 1:
How can the immune system monitor the intracellular enviroment?

How can the immune system detect the intracellular pathogens?
PRR Antigen presentation Display intracellular peptides on the surface of cells Cellular receptors for pathogens and damage-associated molecules are often called pattern recognition receptors (PRRs). They are expressed on the plasma membrane or endosomal membranes of various cell types and also in the cytoplasm of these cells. These various locations of the receptors ensure that the immune system can respond to microbes that may be present outside cells or within different cellular compartments.

Major histocompatibility complex
MHC Major histocompatibility complex cell surface molecules mediate interactions of T cells with antigen presenting cells Major histocompatibility complex (MHC) molecules are expressed on antigen- presenting cells and function to display peptides derived from protein antigens. The cells that capture microbial antigens and display them for recognition by T lymphocytes are called antigen-presenting cells (APCs).

Expressed by all nucleated cells
MHCI Expressed by all nucleated cells the expression is regulated by cytokines or intectious agents. PEPTIDE 1 3 2 2m MHCI molecules are constitutively expressed on virtually all nucleated cells but the expression can be increased by cytokines produced during both innate and adaptive immune responses. All nucleated cells are susceptible to viral infections and cancer-causing mutations. Therefore, it is important that the immune system be able to recognize cytosolic antigens, such as viral antigens and mutated proteins, in any cell type. CD8+ CTLs are the cell population that recognize these antigens and eliminate the cells in which the antigens are produced.

STRUCTURE OF CLASS I MHC MOLECULES
A polymorphic α chain and and a non-polymorph β2 mikroglobulin α1 és α2 domains are responsible for peptide binding MHCI molecules consist of two noncovalently linked polypeptide chains, an α chain (or heavy chain) and a β2-microglobulin. Each α chain is oriented so that about three quarters of the complete polypeptide extends into the extracellular milieu, a short hydrophobic segment spans the cell membrane, and the carboxyl-terminal residues are located in the cytoplasm. The α1 and α2 segments of the α chain interact to form the peptide-binding cleft of class I molecules. Its size is large to bind peptides of 8 to 11 amino acids in a flexible, extended conformation. The α3 segment of the α chain folds into an Ig domain. This segment contains the binding site for CD8 and at the end of the α3 segment is a stretch that traverses the lipid bilayer of the plasma membrane and anchors the MHC molecule. β2-Microglobulin, the light chain of class I molecules interacts noncovalently with the α3 domain of the α chain. Like the α3 segment, β2-microglobulin is structurally homologous to an Ig domain.

Cleft geometry b2-M a-chain Peptide a-chain b-chain Peptide
Each MHC molecule consists of an extracellular peptide-binding cleft, or groove, followed by immunoglobulin (Ig)-like domains and transmembrane and cytoplasmic domains. Class I molecules are composed of one polypeptide chain encoded in the MHC and a second, non-MHC-encoded chain, whereas class II molecules are made up of two MHC-encoded polypeptide chains. Despite this difference, the overall three-dimensional structures of class I and class II molecules are similar. The polymorphic amino acid residues of MHC molecules are located in and adjacent to the peptide-binding cleft. This cleft is formed by the folding of the MHC-encoded proteins. The polymorphic residues, which are the amino acids that vary among different MHC alleles, are located in and around this cleft. This portion of the MHC molecule binds peptides for display to T cells, and the antigen receptors of T cells interact with the displayed peptide and with the α helices of the MHC molecules. Because of amino acid variability in this region, different MHC molecules bind and display different peptides and are recognized specifically by the antigen receptors of different T cells. The nonpolymorphic Ig-like domains of MHC molecules contain binding sites for the T cell molecules CD4 and CD8. CD4 and CD8 are expressed on distinct subpopulations of mature T lymphocytes and participate, together with antigen receptors, in the recognition of antigen; that is, CD4 and CD8 are T cell "coreceptors" . CD4 binds selectively to class II MHC molecules, and CD8 binds to class I molecules. This is why CD4+ helper T cells recognize class II MHC molecules displaying peptides, whereas CD8+ T cells recognize class I MHC molecules with bound peptides. MHC class I accommodate peptides of 8-10 amino acids MHC class II accommodate peptides of >13 amino acids

CYTOSOL-DERIVED PEPTIDES ARE PRESENTED BY MHC-I FOR T-CELLS
14

Degradation of endogenous proteins
takes place in the proteasomes, they are presented on cell surface by MHC I In the class I MHC pathway, protein antigens in the cytosol are processed by the proteasomes. The mechanisms of antigen processing are designed to generate peptides that have the structural characteristics required for associating with MHC molecules and to place these peptides in the same cellular location as the appropriate MHC molecules with available peptide-binding clefts. Peptides generated in the cytosol are translocated by a specialized transporter (transporter associated with antigen processingTAP) into the ER, where newly synthesized class I MHC molecules are available to bind the peptides. On the luminal side of the ER membrane, the TAP protein associates with a protein called tapasin. Peptides translocated into the ER bind to class I MHC molecules that are associated with the TAP dimer through tapasin. Stable peptide-class I MHC complexes that were produced in the ER move through the Golgi complex and are transported to the cell surface by exocytic vesicles. Once expressed on the cell surface, the peptide-class I complexes may be recognized by peptide antigen-specific CD8+ T cells.

MHC do not recognize or distinguish self and nonself peptides
Antigen presentation goes in the absence of pathogen or T cells as well !

Displays intracellular antigens
MHCI Displays intracellular antigens to cytotoxic T cells Cytosolic antigens are processed and displayed by class I MHC molecules, which are expressed on all nucleated cells—again, as expected, because all nucleated cells can be infected with some viruses. Class I–associated peptides are recognized by CD8 + T lymphocytes, which differentiate into CTLs. The CTLs kill the infected cells and eradicate the infection, this being the most effective mechanism for eliminating cytoplasmic microbes.

Tc RECOGNITION OF ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES TCR Peptide
MHCI is expressed by all nucleated cells Peptides of endogenous proteins bind to class I MHC molecules presented to cytotoxic T cells Tc TCR Peptide MHCI Endogenous Ag Ligation of the TCR by MHC-peptide ligands results in the clustering of coreceptors (CD4 and CD8). CD4 and CD8 are T cell coreceptors that bind to nonpolymorphic regions of MHC molecules and facilitate signaling by the TCR complex. CD8 and CD4 interact with class I and class II MHC molecules, respectively, and are responsible for the class I or class II MHC restriction of these subsets of T cells. The Ig domain of CD8 binds to the nonpolymorphic α3 domain of class I MHC molecules. APC

MHCII, presentation of extracellular pathogens antigen presenting cells T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells

System optimalization 2:
MHCI present the intracellular area. Next step, how could the MHC molecules (and the T cells) monitor the extracellular enviroment?

MHCII Expressed by professional antigen presenting cells
Macrophage, dendritic cell, B cell STRUCTURE OF CLASS II MHC MOLECULES PEPTIDE 2 1 2 1 MHCII molecules are expressed on dendritic cells, B lymphocytes, macrophages, and a few other cell types. This pattern of MHC expression is linked to the functions of class I-restricted and class II-restricted T cells. Class II molecules are expressed mainly on these cell types and provide a system for display of peptides derived from extracellular microbes and proteins.

STRUCTURE OF CLASS II MHC MOLECULES
A polymorphic α and a polymorphic β chain 2 1 2 1 PEPTID PEPTIDE Class II MHC molecules are composed of a polymorphic α chain noncovalently attached to a polymorphic β chain. The amino-terminal α1 and β1 segments of the class II chains interact to form the peptide-binding cleft, which is structurally similar to the cleft of class I molecules. The α2 and β2 segments of class II molecules, like class I α3 and β2-microglobulin, are folded into Ig domains. The β2 segment of class II molecules contains the binding site for CD4, similar to the binding site for CD8 in the α3 segment of the class I heavy chain. In class II molecules, the ends of the peptide-binding cleft are open, so that peptides of 30 residues or more can fit. α1 and β1 domens are responsible for peptide binding 22

Cleft geometry b2-M a-chain Peptide a-chain b-chain Peptide
MHC class I accommodate peptides of 8-10 amino acids MHC class II accommodate peptides of >13 amino acids

Presentation of extracellular peptides by MHCII
In the class II MHC pathway, extracellular protein antigens are endocytosed into vesicles, where the antigens are processed and the peptides bind to class II MHC molecules. The initial steps in the presentation of an extracellular protein antigen are the binding of the native antigen to an APC and the internalization of the antigen. Internalized proteins are degraded enzymatically in late endosomes and lysosomes to generate peptides that are able to bind to the peptide-binding clefts of class II MHC molecules. Class II MHC molecules are synthesized in the ER and transported to endosomes with an associated protein, the invariant chain (Ii), which occupies the peptide-binding clefts of the newly synthesized class II molecules. Within the endosomal vesicles, the Ii dissociates from class II MHC molecules and antigenic peptides are then able to bind to the available peptide-binding clefts of the class II molecules . Class II MHC molecules are stabilized by the bound peptides, and the stable peptide-class II complexes are delivered to the surface of the APC, where they are displayed for recognition by CD4+ T cells. 24

Displays extracellular antigens
! ! MHCII Displays extracellular antigens to helper T cells T lymphocytes, on the other hand, can see only peptide fragments of protein antigens, and only when these peptides are presented by specialized peptide display molecules on host cells. How can see T cells the extracellular antigens? By segregating the class I and class II pathways of antigen processing, the immune system is able to respond to extracellular and intracellular microbes in different ways best able to defend against these microbes. Extracellular microbes are captured and ingested by APCs, including B lymphocytes and macrophages, and are presented by class II molecules, which are expressed mainly on these APCs (and on dendritic cells). Because of the specificity of CD4 for class II, class II–associated peptides are recognized by CD4 + T lymphocytes, which function as helper cells. These helper T cells help B lymphocytes to produce antibodies, and they help phagocytes to destroy ingested microbes, thereby activating the two effector mechanisms best able to eliminate microbes that are internalized from the extracellular environment. Neither of these mechanisms is effective against viruses and other pathogens that survive and replicate in the cytoplasm of host cells. 25

MHC do not recognize or distinguish self and nonself peptides
Antigen presentation goes in the absence of pathogen or T cells as well The two antigen presentation pathways function in a parallel simultaneous way A type of MHC molecule presents a lot of different peptides in the same time. Most likely only a few of them, if any, derived form pathogen. (one MHC molecule present only one peptide, millions of MHC present several thousand different peptides) 26

Antigen presentation by MHCII:
Requires professional antigen presenting cells Exogen antigens Helper T cells CD4+ cells 27

RECOGNITION OF EXOGENOUS ANTIGENES BY HELPER T-LYMPHOCYTES
Th Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells TCR Peptide MHCII Exogenous Ag Once expressed on the APC surface, the peptide-class II complexes are recognized by peptide antigen-specific CD4+ T cells, with the CD4 coreceptor playing an essential role by binding to nonpolymorphic regions of the class II molecule. CD4 protein binds to the nonpolymorphic β2 domain of the class II MHC molecule.

MHCII, presentation of extracellular pathogens antigen presenting cells T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells

Macrophage, dendritic cell, B cell
MHCII Expressed by professional antigen presenting cells Macrophage, dendritic cell, B cell PEPTIDE 2 1 2 1

Macrophage, DC MHCII Exogen Ag Fagocytosis PRR or opsonization Degradation of Patogen in the lysosome Peptide MHCII connection APC Dendritic cells are resident in epithelia and tissues capture protein antigens and transport the antigens to draining lymph nodes. During this migration, the dendritic cells mature and become efficient APCs. DCs use receptors to capture and endocytose microbes and their antigens and then process the ingested proteins into peptides capable of binding to MHC molecules. In cell-mediated immune responses, macrophages present the antigens of phagocytosed microbes to effector T cells, which respond by activating the macrophages to kill the microbes. Circulating monocytes are able to migrate to any site of infection and inflammation, where they differentiate into macrophages and phagocytose and destroy microbes. CD4+ T cells recognize microbial antigens being presented by the macrophages and provide signals that enhance the microbicidal activities of these macrophages. Constitutive checking of the extracellular enviroment (fagocytosis, pinocytosis) 31

B cell-mediated antigen presentation
In humoral immune responses, B lymphocytes internalize protein antigens and present peptides derived from these proteins to helper T cells. This antigen-presenting function of B cells is essential for helper T cell-dependent antibody production.

B cell-mediated antigen presentation
B lymphocytes migrate from one secondary lymphoid organ to the next in search of antigen. The activation of antigen-specific B lymphocytes is initiated by the binding of antigen to membrane Ig molecules, which, in conjunction with the associated Igα and Igβ proteins, make up the antigen receptor complex of mature B cells. Antibody responses to protein antigens require recognition and processing of the antigen by B cells, followed by presentation of a peptide fragment of the antigen to helper T cells, leading to cooperation between the antigen-specific B and T lymphocytes. Antigen-activated helper T cells and B cells move toward one another in response to chemokine signals and make contact. In this location, the B cell presents antigen to the T cell, and the B cell receives activating signals from the T cell.

Summary of APCy

Represent the extracellular enviroment
The presentation of cytosolic versus vesicular proteins by the class I or class II MHC pathways, respectively, determines which subsets of T cells will respond to antigens found in these two pools of proteins and is intimately linked to the functions of these T cells. Represent the extracellular enviroment Represent the intracellular enviroment

RECOGNITION OF EXOGENOUS AND ENDOGENOUS ANTIGENES BY T-LYMPHOCYTES
Peptides of endogenous proteins (virus, tumor) bind to class I MHC molecules presented to cytotoxic T cells Th Peptides of exogenous proteins (toxin, bacteria, allergen) bind to class II MHC molecules presented to helper T cells Tc TCR Peptide MHCI TCR Peptide MHCII Endogenous Ag Exogenous Ag Endogenously synthesized antigens, such as viral and tumor proteins, are located in the cytoplasm and are recognized by class I-restricted CD8+ CTLs, which kill the cells producing the intracellular antigens. Conversely, extracellular antigens usually end up in endosomal vesicles and activate class II-restricted CD4+ T cells because vesicular proteins are processed into class II-binding peptides. CD4+ T cells function as helpers to stimulate B cells to produce antibodies and macrophages to enhance their phagocytic activity, both mechanisms that serve to eliminate extracellular antigens. Thus, antigens from microbes that reside in different cellular locations selectively stimulate the T cell responses that are most effective at eliminating that type of microbe. This is especially important because the antigen receptors of CTLs and helper T cells cannot distinguish between extracellular and intracellular microbes. By segregating peptides derived from these types of microbes, the MHC molecules guide CD4+ and CD8+ subsets of T cells to respond to the microbes that each subset can best combat. APC

MHCII, presentation of extracellular pathogens T cell receptor (TCR) Structure Comparision with BCR T cell activation Cytotoxic T cells Helper T cells

The TCR, which recognizes peptide antigens displayed by MHC molecules
T cell receptor (TCR) The TCR, which recognizes peptide antigens displayed by MHC molecules BCR s C H2 H3 V L H H1 The TCR, which recognizes peptide antigens displayed by MHC molecules, is a membrane-bound heterodimer composed of an α chain and a β chain. Each chain containing one variable (V) region and one constant (C) region. The V and C regions are homologous to immunoglobulin V and C regions. Both the α chain and the β chain of the TCR participate in specific recognition of MHC molecules and bound peptides! Antigen recognition is similar for B and T lymphocyte receptors but also differs in important ways. Antibodies can bind many different types of chemical structures, often with high affinities, which is why antibodies can bind to and neutralize many different microbes and toxins that may be present at low concentrations in the circulation. TCRs only recognize peptide-MHC complexes and bind these with relatively low affinity, which may be why the binding of T cells to APCs has to be strengthened by additional cell surface adhesion molecules. The three-dimensional structure of the TCR is similar to that of the Fab region of an Ig molecule. Unlike in antibodies, both TCR chains are anchored in the plasma membrane; TCRs are not produced in a secreted form and do not undergo class switching or affinity maturation during the life of a T cell. Membrane-bound heterodimer composed of an α chain and a β chain, each chain containing one variable (V) region and one constant (C) region Both the α chain and β chains of the TCR participate in specific recognition of MHC molecules and bound peptides

The antigen receptor of MHC-restricted CD4+ helper T cells and CD8+ cytotoxic T lymphocytes (CTLs) is a heterodimer consisting of two transmembrane polypeptide chains, designated TCR α and β, covalently linked to each other by a disulfide bridge between extracellular cysteine residues. These T cells are called αβ T cells. A less common type of TCR, found on γδ T cells, is composed of TCR γ and δ chains. The CD3 proteins are noncovalently associated with the TCR αβ heterodimer, and when the TCR recognizes antigen, these associated proteins transduce the signals that lead to T cell activation. CD3 CD3

T cell receptor and its signal transduction units
Both α and β chains continue into short hinge regions, which contain cysteine residues that contribute to a disulfide bond linking the two chains. These residues interact with negatively charged residues present in the transmembrane portions of other polypeptides (those of the CD3 complex and ζ) that are part of the TCR complex. The CD3 and ζ proteins are noncovalently associated with the TCR αβ heterodimer, and when the TCR recognizes antigen, these associated proteins transduce the signals that lead to T cell activation. The CD3 γ, δ, and Ε proteins are homologous to each other. Each TCR complex contains one TCR αβ heterodimer associated with one CD3 γΕ heterodimer, one CD3 δΕ heterodimer, and one disulfide-linked ζζ homodimer.

MHCII, presentation of extracellular pathogens T cell receptor (TCR) Structure Comparision with BCR T cell activation Cytotoxic T cells Helper T cells

TCRs only function as membrane receptors
B cell Plasma cell TCR Properties of antibodies and T cell antigen receptors (TCRs): Antibodies (also called immunoglobulins) may be expressed as membrane receptors or secreted proteins; TCRs only function as membrane receptors. When immunoglobulin (Ig) or TCR molecules recognize antigens, signals are delivered to the lymphocytes by proteins associated with the antigen receptors. Note that single antigen receptors are shown recognizing antigens, but signaling typically requires the binding of two or more receptors to adjacent antigen molecules. Antibodies serve different functions at different stages of humoral immune responses: membrane-bound antibodies on B cells recognize antigens to initiate the responses, and secreted antibodies neutralize and eliminate microbes and their toxins in the effector phase of humoral immunity. In cell-mediated immunity, the effector function of microbe elimination is performed by T lymphocytes themselves and by other leukocytes responding to the T cells. The antigen receptors of T cells are involved only in antigen recognition and T cell activation, and these proteins are not secreted and do not mediate effector functions. T cell

TCR has a single antigen recognition unit

Citotoxicity Citokine production
Since there is no soluble TCR, effector funcions are mediated by the T cells itself: Citotoxicity Citokine production CD8+ CTLs eliminate intracellular microbes mainly by killing infected cells. In addition to direct cell killing, CD8+ T cells secrete IFN-γ and thus contribute to macrophage activation in host defense and in hypersensitivity reactions. Effector T cells of the CD4+ lineage function by secreted cytokines and cell surface molecules to activate other cells to eliminate microbes. CD4+ T cells also participate indirectly in host defense by helping B lymphocytes to produce high-affinity antibodies against extracellular microbes and by promoting the development of fully functional CTLs that combat intracellular microbes such as viruses.

CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION
Antigen receptor T-CELL B-CELL CHARACTERISTICS OF T-CELL ANTIGEN RECOGNITION The TCR is not able to interact directly with soluble or cell-bound antigen T-cell activation can be induced by antigen in the presence of acessory cells, only ACCESSORY CELL NO INTERACTION ANTIGEN BINDING T-CELL ACTIVATION V C a/b

II ANTIGEN RECOGNITION BY T-CELLS REQUIRES
PEPTIDE ANTIGENS AND ANTIGEN PRESENTING CELLS THAT EXPRESS MHC MOLECULES T II Cell surface MHC-peptide complex T-cell response soluble Ag Peptide antigen Native membrane Ag Cell surface peptides APC T lymphocytes recognize peptide antigens that are bound to and displayed by major histocompatibility complex (MHC) molecules of antigen-presenting cells. T cell receptor recognizes a complex of peptide antigen displayed by a MHC molecule. Major histocompatibility complex (MHC) molecules are expressed on antigen-presenting cells and function to display peptides derived from protein antigens. The cells that capture microbial antigens and display them for recognition by T lymphocytes are called antigen-presenting cells (APCs). APC APC No T-cell response

B cell epitope T cell epitope recognized by B cells proteins
polysaccharides lipids DNA steroids etc. (many artificial molecules) cell or matrix associated or soluble recognized by T cells proteins mainly (8-23 amino acids) requires processing by APC

TCR-BCR similarity: Immunglobulin domain structure
VDJ ---- numerous, randomly generated specificity One cell carries only one specificity Antigen presence--- initiates the clonal expansion of the cells that recognizes it Daughter cells have the same specificity (affinity maturation in B cells) as the progenitor Cells that recognizes self antigen are eliminated in the primary lymphatic tissues (bone marrow, thymus) But TCR do not recognize free antigen, only MHC peptide complex Recognizes only protein antigens No soluble form TCR has a single antigen recognition unit Other effector functions: BCR TCR Neutralization Citotoxicity Opsonization, increase phagocytosis (Citokine production) complement activation NK-cell activation

Macfarlane Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS
Antibodies are natural products that appear on the cell surface as receptors and selectively react with the antigen Lymphocyte receptors are variable and carry various antigen-recognizing receptors ‘Non-self’ antigens/pathogens encounter the existing lymphocyte pool (repertoire) Antigens select their matching receptors from the available lymphocyte pool, induce clonal proliferation of specific clones and these clones differentiate to antibody secreting plasma cells The clonally distributed antigen-recognizing receptors represent about ~107 – 109 distinct antigenic specificities

Macfarlane Burnet (1956 - 1960) CLON SELECTION HYPOTHESIS
Lymphocytes are monospecific cells Antigen engagement result in the activation of lymphocytes Activated lymphocytes differentiate and proliferate but keep their antigen specificity Lymphocytes reacting with self antigen during their development in the primary lymphoid organs, become inactivated or die by apoptosis.

! ! TCR can recognize only the MHC peptide komplex
A portion of the bound peptide is exposed from the open top of the cleft of the MHC molecule, and the amino acid side chains of this portion of the peptide are recognized by the antigen receptors of specific T cells. The same T cell receptor also interacts with polymorphic residues of the α helices of the MHC molecule itself.

T cell response requires the DC-mediated antigen presentation in the secondary lymphoid organs
Antigens that are transported by dendritic cells to the secondary lymphoid organs (e.g. lymph nodes) are recognized by naive T lymphocytes that recirculate through these lymph nodes. The T cells are activated to differentiate into effector and memory cells, which may remain in the lymphoid organs or migrate to nonlymphoid tissues. At sites of infection, the effector cells are again activated by antigens and perform their various functions, such as macrophage activation.

Antigen recognition of T cells

Antigen recognition of T cells
Protein degradation to peptide Peptide-MHC association Peptide/MHC complex expression on the cell surface TCR recognizes the peptide/MHC complex Antigen presenting cell T cell

MHC RESTRICTION The reason that T cells recognize only peptides is that the antigen receptors of CD4+ and CD8+ T cells are specific for antigens that are displayed by MHC molecules, and these molecules can bind peptides but no other chemical structures. Thus, every T cell is specific for a combination of amino acid residues of a peptide antigen plus portions of the MHC molecule. MHC molecules are highly polymorphic, and variations in MHC molecules among individuals influence both peptide binding and T cell recognition. A single T cell can recognize a specific peptide displayed by only one of the large number of different MHC molecules that exist. This phenomenon is called MHC restriction. One single T-cell receptor can recognize a given MHC – peptide complex The TCR-specific peptide is recognized only when its presented with an MHC on which the TCR had been selected during its development in the thymus If the peptide binds to another MHC molecule no T-cell recognition occurs (by this T cell) If the same MHC molecule binds another peptide, no T-cell recognition occurs

Distinct T cell receptors from different microbes
Specificity of innate immunity Specificity of T cells Tc APC peptid MHC Distinct T cell receptors Peptides derived from different microbes

( ) Specificity of innate immunity Specificity of T cells Tc
direct connetion between innate cells and pathogen ( ) Specificity of T cells Tc APC peptid MHC No direct connetion between T cell and pathogen APC-T cell connection Distinct T cell receptors The restriction of T cell recognition to MHC-associated peptides ensures that T cells see and respond only to cell-associated antigens. This is because MHC molecules are cell membrane proteins, and because peptide loading and subsequent expression of MHC molecules depend on intracellular biosynthetic and assembly steps. In other words, MHC molecules can be loaded with peptides only inside cells, where intracellular and ingested antigens are present. Therefore, T lymphocytes can recognize the antigens of intracellular microbes, which require T cell–mediated effector mechanisms, as well as antigens ingested from the extracellular environment, such as those against which antibody responses are generated. Peptides derived from different microbes

Phases of T cell response
(review) Phases of T cell response T cell response The proliferation of T cells is restricted to the secondary lymphoid organs. Antigen is delivered to these organs by DCs IL-2 is the main AUTOKRINE growth factor for T-cells. High affinity IL-2 Rec also upregulated. A similar APC-produced cytokine, IL-15, stimulates proliferation of CD8+ cells, especially memory cells of the CD8+ subset. BEFORE ANTIGEN EXPOSURE frequency of naive T cells specific for any antigen is 1 in 105 to 106 lymphocytes.. AFTER clonal expansion this frequency of all CD8+ T cells specific for that microbe may increase to about 1 in 3 to 1 in 10, representing a >50,000-fold expansion of antigen-specific CD8+ T cells and the number of specific CD4+ cells increases to 1 in 100 to about 1 in 1000 lymphocytes.

Studies in mice first showed this tremendous expansion of the antigen-specific population in some acute viral infections and, remarkably, it occurred within as little as 1 week after infection. Equally remarkable was the finding that during this massive antigen-specific clonal expansion, "bystander" T cells not specific for the virus did not proliferate. Many of the progeny of the antigen-stimulated cells differentiate into effector cells. Effector cells are short-lived, and the numbers of antigen-specific T cells rapidly decline as the antigen is eliminated. After the immune response subsides, the surviving memory cells specific for the antigen number on the order of 1 in 104.

CITOTOXIC T LYMPHOCYTES
cytotoxic T cells CTLs kill targets that express the same class I-associated antigen that triggered the proliferation and differentiation of naive CD8+ T cells from which they are derived and do not kill adjacent uninfected cells that do not express this antigen. Infected or tumoric cells

T lymphocytes recognize
virus-infected cells virus

KILLING OF TUMOR CELLS BY CTL
Cytotoxic T lymphocytes recognize virus-infected or tumor cells The CTL binds and reacts to the target cell by using its antigen receptor, coreceptor (CD8), and adhesion molecules. Within a few minutes of a CTL's antigen receptor recognizing its antigen on a target cell, the target cell undergoes changes that induce it to die by apoptosis. CTLs kill target cells by two main mechanisms: Complexes of perforin and granzymes are released from the CTL by granule exocytosis and enter target cells. The granzymes are delivered into the cytoplasm of the target cells by a perforin-dependent mechanism, and they induce apoptosis. FasL is expressed on activated CTLs, engages Fas on the surface of target cells, and induces apoptosis. After delivering the lethal hit, the CTL is released from its target cell, which usually occurs even before the target cell goes on to die.

MHCII, presentation of extracellular pathogens T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2 Th17 T cells of the CD4+ lineage function by secreted cytokines and cell surface molecules to activate other cells to eliminate microbes. CD4+ T cells also participate indirectly in host defense by helping B lymphocytes to produce high-affinity antibodies against extracellular microbes and by promoting the development of fully functional CTLs that combat intracellular microbes such as viruses. In general, TH1 cells activate macrophages, TH17 reactions are dominated by neutrophils (and variable numbers of macrophages), and TH2 cells recruit and activate eosinophils. Each type of leukocyte is specially adapted to destroy particular types of microbes. This cooperation of T lymphocytes and other leukocytes illustrates an important link between adaptive and innate immunity. There are three distinct subsets of CD4+ T cells, called TH1, TH2, and TH17, that function in host defense against different types of infectious pathogens and are involved in different types of tissue injury in immunologic diseases. The defining characteristics of differentiated subsets of effector cells are the cytokines they produce. The signature cytokines produced by the major CD4+ T cell subsets are IFN-γ for TH1 cells; IL-4, IL-5, and IL-13 for TH2 cells; and IL-17 and IL-22 for TH17 cells

Recognition of the presented antigen induces cytokine production of helper T cells
CD4+ T cells recognize antigens of phagocytosed and extracellular microbes and produce cytokines that activate the phagocytes to kill the microbes and stimulate inflammation. CD8+ T cells can also secrete cytokines and participate in similar reactions. CD8+ cytotoxic T lymphocytes (CTLs) recognize antigens of microbes residing in the cytoplasm of infected cells and kill the cells.

EFFECTOR CD4+ HELPER T LYMPHOCYTES SECRETE DIFFERENT CYTOKINES
IL-4, IL-5, IL-10 Th2 Th0 IFNγ, IL-2, TNF-β/LT Th1 IFNγ IL-4 Differentiated TH1, TH2, and TH17 cells all develop from naive CD4+ T lymphocytes, mainly in response to cytokines present early during immune responses, and differentiation involves transcriptional activation and epigenetic modification of cytokine genes. The cytokines that drive the development of CD4+ T cell subsets are produced by APCs (primarily dendritic cells and macrophages) and other immune cells (such as NK cells and basophils or mast cells) present at the site of the immune response. Differentiation of each subset is induced by the types of microbes which that subset is best able to combat. Each subset of differentiated effector cells produces cytokines that promote its own development and may suppress the development of the other subsets. Inflammatory cytokines CELLULAR IMMUNE RESPONSE Anti-inflammatory cytokines HUMORAL IMMUNE RESPONSE

MHCII, presentation of extracellular pathogens T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2 Th17

Effector function of TH1 cells
IFN-γ is the principal macrophage-activating cytokine and serves critical functions in immunity against intracellular microbes: activates macrophages to kill phagocytosed microbes acts on B cells to promote switching to certain IgG subclasses (IgG2a or IgG2c) and to inhibit switching to IL-4-dependent isotypes (IgE) promotes the differentiation of CD4+ T cells to the TH1 subset and inhibits the differentiation of TH2 and TH17 cells. stimulates expression of several different proteins that contribute to enhanced MHC-associated antigen presentation CD4+ TH1 cells activate macrophages by contact-mediated signals delivered by CD40L-CD40 interactions and by IFN-γ. They stimulate inflammation through the secretion of cytokines, mainly TNF, IL-1, and chemokines, and short-lived lipid mediators such as prostaglandins, leukotrienes, and platelet-activating factor. The collective action of these macrophage-derived cytokines and lipid mediators is to recruit more leukocytes, which improves the ability to destroy infectious organisms.

MHCII, presentation of extracellular pathogens T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2 Th17

TH2 cells stimulate IgE- and eosinophil-mediated reactions that serve to eradicate helminthic infections. TH2 cells secrete IL-4, IL-5, and IL-13, which work cooperatively to eradicate these infections. Roles of TH2 Cells in Host Defense: IgE- and eosinophil-mediated reactions. IL-4 (and IL-13) stimulates the production of helminth-specific IgE antibodies, which opsonize the helminths and promote the binding of eosinophils. IL-5 activates the eosinophils and these cells release their granule contents, which are capable of destroying even the tough integuments of helminths. Activation of mast cells. Mast cells express high-affinity FcΕ receptors and may be activated by IgE-coated helminths and other antigens that bind IgE, resulting in degranulation. The granule contents of mast cells include vasoactive amines, and mast cells secrete cytokines such as TNF and chemokines, and lipid mediators, all of which induce local inflammation that helps to destroy the parasites. Barrier immunity. Cytokines produced by TH2 cells are involved in blocking entry and promoting expulsion of microbes from mucosal organs. For instance, IL-13 stimulates mucus production, and IL-4 and IL-13 may stimulate peristalsis in the gastrointestinal system. Thus, TH2 cells play an important role in host defense at the barriers with the external environment, sometimes called barrier immunity. Alternative macrophage activation. IL-4 and IL-13 activate macrophages to express enzymes that promote collagen synthesis and fibrosis. The macrophage response to TH2 cytokines has been called alternative macrophage activation to distinguish it from the activation induced by IFN-γ. Macrophages that are activated by TH2 cytokines contribute to tissue remodeling and fibrosis in the setting of chronic parasitic infections and allergic disease. Alternatively activated macrophages may also serve to initiate repair after diverse types of tissue injury that may not involve infectious agents or immune responses; in these situations, the activating cytokines, such as IL-4, may be produced by eosinophils and other cell types in tissues. Alternatively activated macrophages induce the formation of fibrous tissue by secreting growth factors that stimulate fibroblast proliferation (platelet-derived growth factor), collagen synthesis (transforming growth factor-β [TGF-β]), and new blood vessel formation or angiogenesis (fibroblast growth factor). TH2 cytokines suppress classical macrophage activation and interfere with protective TH1-mediated immune responses to intracellular infections. Suppression of classical macrophage activation is, in part, because IL-4 stimulates production of cytokines such as IL-10 and TGF-β that inhibit TH1 development and function.

MHCII, presentation of extracellular pathogens T cell receptor (TCR) T cell activation Cytotoxic T cells Helper T cells Th1 Th2 Th17 TH17 cells secrete cytokines that recruit leukocytes, mainly neutrophils to sites of infection. Neutrophils are a major defense mechanism against extracellular bacteria and fungi, TH17 cells play an especially important role in defense against these infections.

IL-1 and IL-6 produced by APCs and transforming growth factor-β (TGF-β) produced by various cells activate the transcription factors (RORγt and STAT3) which stimulate the differentiation of naive CD4+ T cells to the TH17 subset. IL-23, which is also produced by APCs, especially in response to fungi, stabilizes the TH17 cells. TGF-β may promote TH17 responses indirectly by suppressing TH1 and TH2 cells, both of which inhibit TH17 differentiation. IL-21 produced by the TH17 cells amplifies this response.

EFFECTOR T LYMPHOCYTES
Cytotoxic+ T-cells EFFECTOR T LYMPHOCYTES

MHCI is present in all the nucleated cells
Intracellular pathogens can be presented on all the cells Any cell is infected, can be killed by cytotoxic T cells MHCII present extracellular antigens to helper T cells. Helper T cells direct the immune response by the pruduced cytokines.

T cells Abul K. Abbas: Basic Immunology page 49-71 (fig3.7, 3.9, 3.11, 3.16 are not required) and 105-115 (fig 5.11, 5.18 are not required)

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Presentation on theme: "T cells Abul K. Abbas: Basic Immunology page 49-71 (fig3.7, 3.9, 3.11, 3.16 are not required) and 105-115 (fig 5.11, 5.18 are not required)"— Presentation transcript:

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T cells Abul K. Abbas: Basic Immunology page 49-71 (fig3.7, 3.9, 3.11, 3.16 are not required) and 105-115 (fig 5.11, 5.18 are not required)

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Presentation on theme: "T cells Abul K. Abbas: Basic Immunology page 49-71 (fig3.7, 3.9, 3.11, 3.16 are not required) and 105-115 (fig 5.11, 5.18 are not required)"— Presentation transcript:

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