Presentation on theme: "The life history of T lymphocytes"— Presentation transcript:
1 The life history of T lymphocytes Precursors mature in the thymusNaïve CD4+ and CD8+ T cells enter the circulationNaïve T cells circulate through lymph nodesand find antigensClonal expansion;differentiation into effector and memory cellsEffector T cells migrate to sites of infectionEradication of infection
2 Lecture outlineProperties and functions of subsets of CD4+ effector T cells; functions of cytokinesActivation and functions of CTLsCell-mediated immunity: T cell-mediated defense against intracellular microbesMigration of T cells; activation of phagocytes and other leukocytes by effector T cells
3 Functions of CD4 helper T cells, the master controllers of immune responses, are mediated by cytokines
4 Discovery of Th1 and Th2 subsets Immune responses to mycobacteria and helminths are very different but CD4+ T cells are required for bothHow can the “same” CD4+ T cells trigger such distinct reactions?
5 Discovery of Th1 and Th2 subsets Immune responses to mycobacteria and helminths are very different but CD4+ T cells are required for bothHow can the “same” CD4+ T cells trigger such distinct reactions?Hypothesis: CD4+ T cells consist of subpopulations that mediate different responsesIdentification of mouse CD4+ Th1, Th2 clones that produce distinct cytokines
6 The discovery of the Th17 subset The first two subsets were identified on the basis of distinct cytokine profiles and were called type 1 and type 2 helper cells (Th1 and Th2)Many inflammatory diseases (mouse models first) thought to be caused by Th1 cells were not prevented by eliminating Th1 cells or their cytokinesLed to the discovery of the Th17 subset (annoying nomenclature!)
7 CD4+ TH subsetsAbbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011cElsevier
8 CD4+ T cell subsets: definitions and general properties Populations of CD4+ T cells that make restricted and non-overlapping sets of cytokinesEarly after activation, T cells can produce multiple cytokinesProgressive activation leads to “polarization”: production of selected cytokinesDistinct functions, migration properties, roles in disease
9 Effector functions of TH1 Cells TH1 cells stimulatephagocyte-dependent host defense, the defense mechanism that works against most bacteria and viruses that enter tissues and are ingested by phagocytes
10 Development of TH1 cells Th1 cells develop inresponse to microbesthat activate dendriticcells and macrophages(most ingested bacteria and viruses).
11 Effector functions of TH2 Cells Antibody productionIgG4 (human),IgG1 (mouse)Th2 cells combathelminths, providedefense at mucosal barriers (“barrierimmunity”), and are involved in allergic reactions.
12 Development of TH2 cells Th2 cells develop in response to organisms that induce the local production of IL-4 and do not activate macrophages and dendritic cells strongly.
13 Effector functions of TH17 Cells Th17 cells combat extracellular bacteria and fungi.These microbes activate DCs to produce Th17-inducing cytokines.Th17 cells are also involved in many inflammatory diseases.Chemokines, TNF, IL-1, CSFsInflammation
14 Helper T cell subsetsCD4+ helper T cells orchestrate specialized immune responses to different types of microbesThe development of different Th subsets is driven by cytokines produced by APCs and other cells when naïve CD4 cells are being activatedEach subset is induced by the types of microbes that subset is designed to combatOnce a subset is generated, it makes cytokines that induce more of the same and shut off the others --> polarization of the immune response towards increasing specialization (a feature of adaptive immunity)
15 Genetic proof for the importance of different T cell subsets in humans Mutations affecting IL-12/IFN-g cytokines or receptors defective Th1 responses atypical mycobacterial infectionsMutations affecting Th17 development or IL-17 mucocutaneous candidiasis and bacterial abscesses (“Job’s syndrome”)
16 Roles of T cell subsets in disease Th1: autoimmune and inflammatory diseases (IBD?, MS?, RA?); tissue damage in infections (e.g. Tb)Activation of macrophages, CTL responses; production of injurious antibodiesTh2: allergies (e.g. asthma)Stimulation of IgE responses, activation of eosinophilsTh17: inflammatory diseases (MS, IBD, RA, psoriasis)Recruitment of leukocytes (inflammation)
17 The balance of Th1 and Th2 responses determines the outcome of some infections
18 Cytotoxic (cytolytic) T lymphocytes (CTLs) CD8+ CD4- cells that recognize class I MHC-associated peptides derived from cytoplasmic protein antigens in any nucleated cellEffector functions:Killing of infected cells (microbes in cytoplasm), tumor cells (tumor antigens in cytoplasm)Secretion of IFN-g --> activation of macrophages (when microbes escape into cytoplasm and antigens enter class I MHC pathway)
19 Mechanisms of killing of infected cells by CD8+ CTLs CTLs “inject” their granulecontents into target cellsthrough membrane “pores”;major granule contents areenzymes that activatecaspases and induceapoptotic death of thetarget cells, i.e. help thetarget cells to commitsuicide
20 Cell-mediated immunity against the intracellular bacterium Listeria monocytogenes In defense against intracellular microbes,T cells provide specificity and activate phagocytes, phagocytes kill the bacteria
21 Cell-mediated immunity (CMI) Defense against intracellular microbesMediated by T lymphocytesCD4+ T cells activate phagocytes (macrophages and neutrophils), eosinophilsCD8+ T cells kill infected cells, activate macrophagesT cell-mediated leukocyte recruitment and macrophage activation also cause delayed type hypersensitivity (DTH), which may have injurious effects
22 Stages in the development of T cell responses: induction
23 Stages in the development of T cell responses: effector phase
24 Migration of naïve and effector T cells Naïve T cells migrate preferentially to secondary lymphoid organs,previously activated T cells to sites of infection and inflammation.Cell migration is regulated by adhesion molecules and chemokines.
25 Retention of effector T cells at sites of infection T cells are retainedat sites of antigen recognition inperipheral tissues, because antigen recognition stimulates expression of high-affinity adhesion receptors (integrins) that bind to extracellular matrix
26 Determinants of migration of naïve and effector T cells Naïve T cells:L-selectin: binds to HEV in lymph nodesCCR7: recognizes chemokines made in peripheral lymphoid organs (lymph nodes, spleen, etc)Effector T cells:Ligands for E- and P-selectins: bind to endothelium at sites of infectionVarious chemokine receptors: recognize chemokines made at sites of infectionIncreased expression of integrins: bind to extracellular matrix proteins
27 Functions of CD4+ T cells are mediated by CD40-ligand and cytokines Mutations of CD40L (orCD40) are the cause of ahuman diseaseassociated with defects inantibody responses and CMIRequirement for cell-cell contact ensures T cells recognize macrophages or B cells with the relevant antigenTherapeutic applications:inhibit abnormal immuneresponses, graft rejectionwith anti-CD40L antibody
28 Activation of macrophages by T cells T cells (via CD40L, IFN) stimulate production of microbicidal substances in macrophages -- make phagocytes better able to kill what they eat.
29 Functions of activated macrophages in CMI Macrophage response Role in CMIProduction of reactive oxygenspecies, nitric oxide,lysosomal enzymesKilling of microbes inphagolysosomes (maineffector function)Secretion of cytokines (TNF,IL-1, chemokines, others)Leukocyte recruitment(inflammation)Increased expression ofB7 costimulators, MHCmoleculesIncreased T cellactivation (adaptiveimmunity)Macrophages are activated by TLR recognition of microbes as part of innate immunity; T cells activate them more
30 Classical and alternative macrophage activation
31 The life history of T lymphocytes Precursors mature in the thymusNaïve CD4+ and CD8+ T cells enter the circulationNaïve T cells circulate through lymph nodesand find antigensClonal expansion;differentiation into effector and memory cellsEffector T cells migrate to sites of infectionEradication of infection