醫(yī)學(xué)免疫學(xué)t課程cell and mediated immunity

1、T cell and Cell-mediated immunityLie Wang (汪洌）浙江省杭州市浙江大學(xué)紫金港校區(qū)醫(yī)學(xué)院科研樓A810-814醫(yī)學(xué)院免疫學(xué)研究所 Development of T cells T cell surface markers T cell subsets Functions of T cells Cell-mediated immunityContents T lymphocyte:a key regulator of the immune systemAbsence or hyperactivation of T cells leads to immuno

2、deficiency, respectively chronic inflammation or autoimmune disorders.CD4 T cellCD8 T cell1. Factors promoting T cell development in the thymusn Cytokines (IL-1, IL-6, IL-7) and hormones secreted by thymic stroma cells and thymocytes themselves.n Interaction of cell adhesion molecules between immatu

3、re thymocytes and thymic stroma cellsThe thymus, which lies in the midline of the body, above the heart, is made of several lobules, each of which contains discrete cortical (outer) and medullary (central) regions. The cortex consists of immature thymocytes (dark blue in the cartoon) that are closel

4、y associated to branched cortical epithelial cells (pale blue), and scattered macrophages (yellow) that clear apoptotic thymocytes. The medulla, in contrary consists of mature thymocytes (dark blue), medullary epithelial cells (orange) along with macrophages (yellow) and dendritic cells (branched, y

5、ellow). Thymocytes in the outer cortical layer are proliferating immature cells, while cells of the deeper cortical layer (cortico-medullary junction) undergo thymic selection. Geography of the thymus:Thymic epithelial cells control the maturation of thymocytesThe nude mouse strain is athymic due to

6、 a mutation in the Foxn1nu gene that encodes FOXN1, a transcription factor of the forkhead box family. FOXN1 is preferentially expressed in the skin and thymus. Alteration of itsexpression in the thymus underlies the manifestation of severe immunodeficiency resulting from total absence of T cell dev

7、elopment. The cortical epithelium of the thymus is critical for T cell developmentThymusPeripheryThymocyte differentiationCD4+8+CD4sp+CD8sp+CD4T+CD8T+Cytotoxic HelperMHCIIMHCIIMHCIMHCICD4-8-n Pre-T cells no T cell marker expressionn Double negative cells (DN) CD4-CD8-; cytoplasmic CD3+n Double posit

8、ive cells (DP) CD4+CD8+, CD3+, TCRlow, TCRlow n Mature T cells (single positive T cells) CD4+ or CD8+, CD3+, TCR+Mousethymus5 x 107 per dayT cells mature in the thymus but most die there.98% of cells die in the thymus without inducing any inflammation or any change in the size of the thymus.Thymic m

9、acrophages phagocytose apoptotic thymocytes.2 x 106 per dayConstant1-2 x 108cells Central tolerance is the mechanism by w h i c h n e w l y developing T cells a n d B c e l l s a r e r e n d e r e d n o n -reactive to self during their development in thymus and bone marrow.MechanismsCentral toleranc

10、e It is all about the right range Too little Just right Too muchPositive selection: During positive selection Double-Positive T cells that can recognize self MHCs are selected for proliferation, and those T cells that do not recognize self MHC die via Apoptosis. Positive selection also assures TCR t

11、o recognize peptide/MHC complex and also go with the appropriate CD4 or CD8. For example, TCRs specific for MHC II need to retain CD4, and lose CD8. If the reverse occurs, they will die via apoptosis. The same is true for the T cells that are specific for MHC I, which need to retain CD8, and lose CD

12、4.Thymocytes are positive selected by MHC/self peptidesNegative selection: T cells that are strongly activated by self MHC plus self peptides need to be eliminated in the thymus. complex.If they escape this elimination, they may subsequently react against self antigens, and cause Autoimmune disease.

13、Central Tolerance is achieved by negative selectionn Positive selectionDP cells that bind, with moderate affinity, to MHC-Ag on thymic stroma cells survive-MHC restrictionMHC I-CD8+ T cellsMHC II-CD4+ T cellsn Negative selectionCells that bind to MHC-Ag on thymic stroma cells (or auto-reactive T cel

14、ls, ART) will undergo apoptosisFormation of central immune toleranceDownloaded from: StudentConsult (on 1 June 2006 01:58 PM) 2005 Elsevier CDs related to T cell activationCD3分子與T細(xì)胞受體組成TCRCD3復(fù)合物，分布于T細(xì)胞和部分胸腺細(xì)胞表面，在TCR信號轉(zhuǎn)導(dǎo)過程中起著關(guān)鍵作用。CD3分子由、和五種鏈形成的6條鏈組成。胞漿區(qū)有“免疫受體酪氨酸活化基序” (immunoreceptor tyrosine-based ac

15、tivation motif，ITAM)結(jié)構(gòu)，其中的酪氨酸磷酸化后，可活化有關(guān)激酶，轉(zhuǎn)導(dǎo)TCR-CD3介導(dǎo)的活化途徑的信號。1.Consists of 5 proteins that are designated as , , , and .Three dimers: , , ()2.The cytoplasmic domain contains ITAM (immunoreceptor tyrosine-based activation motif) YxxL/V3.Function: transduction of signals that lead to T cell activatio

16、n.*CD4: first and second domains bind to nonpolymorphic region of MHC molecules* CD8: IgV-like domain of chain binds to nonpolymorphic 3 region of MHCmolecules *介導(dǎo)細(xì)胞間的粘附作用介導(dǎo)細(xì)胞間的粘附作用 *參與參與TCR-CD3信號傳導(dǎo)信號傳導(dǎo) APCT細(xì)胞細(xì)胞CD28: provide an co-stimulatory signal for T cell CTLA-4:suppress amplification of activa

17、ted T cell (bring into play negative regulation ）ICOS: expressed on activated T cellsCD2: SRBC receptor, LFA-2 PD-1:ligand PD-L1,PD-L2LFA-1 and ICAM-1: mediate adhesion between APC (or target cells or endothelial cells) and T cells or other leukocytes. 1Naive T cells, effector T cells and memory T c

18、ells 2TCR T cells and TCR T cells3CD4+T and CD8+T cells4Th, Tc and TregPerforinGranzymeCD8 T cellsPeptide+MHC IVirally infected cellCD8 CytokinesIFNCD4 T cellsPeptide+MHC IIIFNCD40CD40LB cellCD4 CytokinesIL-4CD8+CD4+Effector and regulatory CD4+ T cell subsets involved in achieving the balance betwee

19、n the anti-infective immune response and host pathology.CD25-PEPeripheral T cell toleranceLack of CD4+FoxP3+ Tregs leads to AI disease in FoxP3-/- or Scurfy MiceAlexander Y. RudenskyUniversity of WashingtonShimon SakaguchiKyoto University，RIKENPeripheral T cell tolerance Interleukin 17-producing CD4

20、+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages Nat Immunol, 6:1123-32, 2005. Casey T. Weaver, M.D. University of Alabama at Birmingham In 2005, Casey Weavers team identified a third class of T helper cell that produces the cytokine interleukin 17 (IL-17) in

21、 response to autoimmune tissue injury, which they named TH17 cellsCell 2006, 126: 11211133Nat Immunol. 2007,8(4): 345-3501. CD4+ helper T cells (Th)Th0:Th cells that secrete broad spectrum of cytokines at low level.Th1: produce IL-2 and IFN- , but not IL-4. They are chiefly responsible for cell-medi

22、ated immune responses, but can also help B cells to produce IgG2a, but not much IgG1 or IgE;Th2: secrete IL-4, 5, 10, 13, but not IL-2 and IFN- , are very efficient helper cells for production of antibody, especially of IgG1 and IgE ;Function: directly kill target cells (cytotoxicity)Mechanisms: 1.

23、Cytolysis (necrosis) - three stages: a. contact phase: recognition of antigen in the context of MHC class I molecules b. secretory phase: release of cytolytic granules (perforin and granzymes) c. lysis phase: osmotic death 2. Cell apoptosis a. FasL-Fas: CTLs express FasL interaction with Fas on targ

24、et cells activation of caspase 8 apoptosis b. Granzymes caspase 10 apoptosis Cell-mediated immunity is the arm of the adaptive immune response whose role is to combat infection of intracellular pathogens, such as intracellular bacteria (mycobacteria, listeria monocytogens), viruses, protozoa, etc. T

25、hree phasesuAntigen recognition phaseuActivation ,proliferation and differentiation phaseuEffector phase1 Ag presentation by APC Non specific binding of APC and Tcell Specific binding of APC and T cell TCR-peptide-MHC co-receptor-MHC co-stimulatory molecules T cell synapse or immunological synapse L

26、igand-receptor pairs involved in T cell activation Main costimulatory molecules mediating interactions between T cells and APCs The first signal TCR-antigen peptide-MHC (double recognition) CD4-MHC II or CD8-MHC I The second signal (co-stimulatory signal) Interactions between co-stimulatory molecule

27、s on APC and corresponding receptors on T cells CD28/CTLA-4 B7, LFA-1ICAM-1, CD2LFA-3 Cytokines in T cell activation IL-1,2,6,12 1.Synapse formation2.Activation of Src family PTK(p59fyn, p56lck)3.Phoisphorylation tyrosine of CD3 ITAM4.Recruitment and activation of Syk family PTK(ZAP-70)5.Phoisphoryl

28、ation of adaptor LAT and SLP6.Activation of TF:NFAT, AP-1, NF-B, Oct-17.Transcription and expression of gene :IL-2 et al1) CD4+ T cells: Th, Tr, Treg,Th17,Tm regulated by cytokines2) CD8+ T cells: Tc Th-dependent Th-independent: virus infected DC that highly express co-stimulatory molecules can dire

29、ctly stimulate CD8+ T cells. Activation of CD8+ T cells1) CD4+ T cells Th1: secrete IFN- , etc. express CD40L express FasL, kill Fas+ target cells effect on lymphocytes: IL-2 effect on neutrophil: TNF- , Th2: promote B cell growth and Ig production mediate hypersensitivity Th17: IL-17,IL-8,TNF- : enhance leukocyte recruitment and inflammation Activate macrophages Two types of cell-mediated immunityCytotoxicity: kill target cells a. necrosis: perforin an