Download presentation
Presentation is loading. Please wait.
1
Antigen presentation in a nutshell
2
ANTIGEN-SPECIFIC T – CELL ACTIVATION MHC – peptide complex (ligand)
PARTNERS Antigen presenting cell carrying antigenic peptides bound to MHC – pre-formed MHC – peptide complexes – INDEPENDENT OF T CELLS Self MHC with captured antigenic peptide interacts with antigen-specific T lymphocytes selected from the available T cell repertoire INTERACTION MHC – peptide complex (ligand) T cell receptor
3
MHC RESTRICTION One single T-cell receptor can recognize a given MHC – peptid 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 If the same MHC molecule binds another peptide, no T-cell recognition occurs
4
THE EXPERIMENT OF DOHERTY & ZINKERNAGEL 1976
Virus B + Y cells T Virus A T - CELLS T Specific for self and virus MOUSE Y Virus A + Y cells T MOUSE X Virus A + X cells T Virus A + X cells T The virus infected cell must derive from the same strain as the T cell They have to be MHC identical M e d i a G r a p h i c s I n t e r n a t i o n a l
5
RECOGNITION OF CORRECT MHC – PEPTIDE COMPLEXES BY THE SPECIFIC T-CELL
Infected cell Normal cell T APC AND T CELL INTERACTION IS IT SUFFICIENT FOR T CELL ACTIVATION? WHERE AND WHEN CAN OCCUR? HOW IS IT INDUCED?
6
VARIABILITY AND ORIENTATION OF CDR IN THE T CELL RECEPTOR
-chain -CHAIN Diszulfid hidak CDR1 CDR CDR3 -chain V C CDR1 and CDR2 are not hypervariable NO SOMATIC HYPERMUTATION Variability of CDR3 is the result of joining variability CDR1 CDR CDR3
7
INTERACTION OF THE T - CELL ANTIGEN RECEPTOR WITH AN MHC – PEPTIDE COMPLEX
TCR - MHC1 TCR - MHC1 CDR3 - peptide The TCR is monovalent, binds a single MHC – peptide complex The affinity of the TCR – peptide – MHC interaction is low M/l A defined MHC – antigenic peptide complex is displayed in the cell membrane together with various other MHC – peptide complexes (DILUTED LIGAND) most complexes are MHC/peptide complexes How many MHC – peptide complexes are needed for T cell signaling? Approx 100 MHC/peptide compl. Is needed for target cell lysis by CD8 T cells. About 0.1% of total MHCI present on an average cell. MOST COMPLEXES ARE MHC SELF PEPTIUDE COMPLEXES…
8
THE IMMUNOLOGICAL SYNAPSE
10
THE IMMUNOLOGICAL SYNAPSE
ANTIGEN PRESENTING CELL ICAM-1 LFA-1 B7 CD28 CD48 CD4 T CELL CD2 SIGNALING COMPLEX adaptor ICAM – Intercellular Adhesion Molecule ACTIVATED T CELL
11
T CELL RECEPTOR MEDIATED SIGNALING
Multisubunit Immune Recognition Receptors MIRR α β ε δ ε γ ζ ζ ITAM Immunoreceptor Tyrosine-based Activation Motif ACTIVATION
12
The T cell receptor is a complex of antigen specific α and β chains associated in the membrane with the CD3 γ, δ, ε and ζ chains. Each of the CD3 chains has at least one copy of a signaling motif, the immunoreceptor tyrosine-based activation motif or ITAM, in its cytoplasmic domain. T cell activation requires the interaction of other molecules, such as CD45, whose cytoplasmic domain contains a tyrosine phosphatase enzyme, and the T cell coreceptor, either CD4 or CD8. In this example the coreceptor is CD4. The coreceptor molecules have the tyrosine kinase, Lck, bound to their cytoplasmic domains. Lck is attached to CD4 by a zinc ion, which bridges cysteine residues in each molecule. A phosphorylated tyrosine at one end of Lck is bound to an internal SH2 domain. This locks the kinase domain into an inactive conformation. In this example, the T cell is a CD4 T cell and its antigen receptor recognizes an MHC class II molecule together with its bound peptide. When the T cell receptor binds its specific MHC:peptide complex, a number of events take place within the cell. CD45 dephosphorylates the terminal tyrosine of Lck and initiates its kinase activity. CD4 interacts with the MHC, bringing Lck into close proximity with the ITAMs of the other T cell receptor. Activated Lck then phosphorylates the ITAMs of the TCR. At this point, the tyrosine kinase ZAP70 is recruited to the phosphorylated ITAMs of the TCR and binds with specificity through its two SH2 domains. Now bound to the ITAMs of the TCR, ZAP70 is then phosophorylated in turn by activated Lck. With ZAP70 now located in proximity to the inner cell membrane, it is able to phosphorylate LAT, a transmembrane protein with a large intracytoplasmic domain. When LAT is phosphorylated, the adaptor protein GADS binds to LAT and recruits SLP-76, a cytoplasmic protein, to form a large scaffold. This scaffold will then be used in the subsequent activation of PLCγ. While this scaffold can be generated by signaling through the TCR alone, subsequent events, including the activation of PLCγ, require contributions of other costimulatory pathways involving CD28.
13
TCR signalling Fyn
14
APC T cell
15
THE INTERACTION OF T CELLS AND ANTIGEN PRESENTING CELLS
recognition 1 2 3 4 5 6 7 8 stabilization separation Negulescu P.A. et. al. Immunity 4: , 1996
16
Role of transcription factors in T-sejt activation
17
TCR signaling
18
THE CONTACT OF APC AND T CELLS IS STABILIZED BY ADHESION MOLECULES
MHCI – CD8 MHCII – CD4 CD40 – CD40L B7 – CD28 * B CELL T CELL
19
KINETICS OF LYMPHOCYTE ACTIVATION
ANTIGEN SIGNAL1. Nyugvó limfocita G0 sejtosztódás DNA synthesis Effector cell Memory cell Transport Membrane change RNA and protein synthesis Resting lymphocyte G0 co-receptor Adhesion molecule Cytokines SIGNAL2. Resting lymphocyte G0 PTK activation RNA synthesis Free Ca Protein synthesis Protein phosphorylation DNA synthesis Lymphoblast 0 10sec 1min 5min hr hrs hrs hrs
20
INVOLVEMENT OF ADHESION AND CO-STIMULATORY MOLECULES
INTERACTION OF THE TCR WITH MHC-PEPTIDE COMPLEXES IS ESSENTIAL BUT NOT SUFFICIENT FOR T-CELL PRIMING INVOLVEMENT OF ADHESION AND CO-STIMULATORY MOLECULES CONVERGING SIGNALING PATHWAYS IN T CELL ACTIVATION CD4/CD8 costimulation CD28 costimulation
21
THE ADHESION AND CO-STIMULATORY MOLECULES CD4 AND CD8
MARKERS OF T CELL SUBPOPULATIONS ADHESION MOLECULE BINDS TO MHC SIGNALING MOLECULE TARGET CELL 1 3 2 2m 2 1 2 1 PROFESSIONAL APC CD8 Cytotoxic T-cell α β Helper T-cell CD4 SIGNAL
22
THE RATIO OF CD4+/CD8+ T CELLS IS STABLE IN HEALTHY INDIVIDUALS
Normal CD4+ T-cell counts = 600 – 1400/ l HIV infection AIDS = CD4+ T cell count <200/l
Similar presentations
