Naïve T cells

1. effector T cells APC Naïve T cells effector T cells Ag Target cells

2. Naive T cells encounter antigen during their Recirculation through peripheral lymphoid organs Naïve T cells circulate from bloodstream through lymphoid organs and back to bloodstream, making contact with many thousand APC in lymphoid tissue: • Survival signals: re-enforce the positive selection • by MHC: self peptide 2. Ensure the high probability of encountering pathogens, Only one in 104-106 is to be specific for particular Ag

4. Activation of naïve T cells required three signals delivered from APC CD28-B7 induce T cells express growth factor IL-2 and its high affinity receptor (CD25, IL2Ra)

5. T cell activation and Cell Mediated Effector Response • Entry of naïve T cells and APC cells into • peripheral Lymphoid organs 2. The production of armed effector T cells 3. General properties of armed effctor T ells. 4. T ell mediated cytotoxicity 5. Macrophage activation by armed CD4 Th1 cells

6. Entry of naïve T cells and APC cells into peripheral Lymphoid organs 1. Lymphocytes entyry into lymphoid tissues -------Adhesion molecules -------Chemokines 3. Antigen presentation cells

7. Distinct stages for lymphocytes entry into lymph node require the activity of adhesion and chemokines CCL21:CCR7 (T cells) CXCL12:CXCR4 (Tcells)

8. Lymphocyte migration, activation, and effector function depend on cell-cell interaction mediated by cell adhesion molecules Adhesion molecules: 1.Selectin, integrin, members of Ig superfamily, mucin like molecules 2.Broad role in generation of lymphocyteresponse 3.migration, effector T cells-target cells, getting lymphocyte together; B-T cell interaction

9. L-Selectin and mucin like vascular addressins Selectin: lymphocyte homing to particular tissue leukocyte: L selectin (blood to lymph tissue), vascular endothelium : P-or E- selectin (blood to infection sites) Cell surface sugar group : Vascular addressins: CD34, GlyCAM-1 Sulfated Sialyl-LewisX

10. Integrins are important in T-lymphocyte adhesion ab, subfamily (large a, common b), b2, leukocyte integrins, all T cells, known as LFA -1(lymphocyte function associated antigen-1) , most important one, naïve and effector T cell migration b1, leukocyte integrins, late stage in T cell activation, very late activation antigen (VLA), armed effector T cell to infection sites

11. Integrins are important in T-lymphocyte adhesion Integrins: (development, inflammatory response) 1.cell-cell, cell-extracellular matrix; signals induce intergrin bind to their ligand tightly: a. chemokine enhance integrin binding to its ligand ex: CCL21 (SLC; secondary lymphoid tissue chemokines) expressed by DC, stromal cells, high vascular endothelium cells, bind to CCR7, (naïve T cell to lymphoid tissue) b. T cell receptor trigger T cell integrin-ligand tightly

12. Ig domain Adhesion molecules involved in leukocyte interactions Ig domain superfamily: CD4, CD8, CD19, intercellular adhesion molecules (ICAM) ICAM-1.2.3 ICAM1,2: endothelium cells, lymphocytes, ICAM3: naive T cells LFA: lymphocyte function association antigen

13. CCR7 Lymphocytes in the blood enter lymphoid tissue by crossing the walls of high endothelium venules 血球滲出 CCL21 CCL21 CCL18

14. Entry of naïve T cells and APC cells into peripheral Lymphoid organs 1. Lymphocytes entry into lymphoid tissues -------Adhesion molecules -------Chemokines 2. Antigen presentation cells

15. Antigen presenting cells Dendritic cells vs Macrophage vs B cells Selectivity of antigen uptake Antigen process prosperities, costimulatory molecules, Migration behavior Distinct function of APC in initiating T cell response

16. Antigen-presenting cells are distributed differentially in the lymph node Dendrtic cells: T cell area a wide variety pathogens Macrophage: Marginal sinus, (lymph afferent), medullary cord (Lymph efferent) T cell areas ingested pathogens B cells: lymphoid follicles soluble antigens (toxin) B cells as APC require: 1. Appropriate receptor (internalize) 2. Antigen at high density

17. Two different functional classes of dendritic cells cDC pDC cDC: CD11c+: activation of naive T cells pDC: sentinels哨兵 primarily for virus infection and produce a lot of IFNa and b less efficiency in priming naïve T cells, TLR7 and TLR9 for sensing virus infection

18. Dendritic cells process pathogens via different routes DC are susceptible to infection by quite a number of viruses

19. Dendritic cells mature through at least two definable stages to become potent antigen-presenting cells in lymphoid tissue

20. Dendritic cells mature through at least two definable stages to become potent antigen-presenting cells in lymphoid tissue Inflammatory response: ----transport antigen to the local lymphoid tissue ---- Enable APC to present antigen effectively to naïve T cells. 1. The ability to activate T cells Lymphoid>>>epithelial and solid organs 2. Immature dendritic cells: Low MHC, No B7 phogocytosis: using DEC250 receptor Macropinocytosis (non-specific) Induce tolerance to self antigen 3. Mature dendritic cells: High level: MHC, adhesion adhesion molecules, DC-SIGN, chemokine (DC-CK CCL18, attract naïve T cells),CCR7 (chemokine receptor, homing to lymphoid org.), IL-12

21. Macrophage are scanvenger cells that can be induced by pathogens to present foreign antigens to naïve T cells Kupper cells and Macrophage in spleen :little MHC II and No TLR Resting macrophage: Little or no MHCII NO B7 Insoluble antigen Microbial substances can induce co-stimulatory activity in macrophages Adjuvant

22. B cells are highly efficient at presenting antigen that bind to their surface immunoglobulin B cells: soluble antigen, constitutively high levels of MHC II, induced B 7.2 by microbial Protein How important of B cells as APCs? vs Dendritic cells Soluble antigens are not abundant during natural infection B cells can use their immunoglobulin receptor to enhance the presentation of specific antigen very efficiently to T cells

23. Summary of APC The properties of the various antigen-presenting cells

24. T cell activation and Cell Mediated Effector Response • Entry of naïve T cells and APC cells into • peripheral Lymphoid organs 2. The production of armed effector T cells (Priming) 3. General properties of armed effector T ells. 4. T ell mediated cytotoxicity 5. Macrophage activation by armed CD4 Th1 cells

25. Cell-surface molecules of the Ig superfamily are important in the interactions of lymphocytes with antigen-presenting cells DC-sign: lectin only dendritic cells CD58: also known as LFA-3 The initial interaction of T cells with APC is mediated by cell-adhesion molecules ICAM3: LFA1 and DC-Sign Synergize redundancy

26. The initial interaction of T cells with antigen-presenting cells is mediated by cell adhesion molecules Transient adhesive interactions between T cells and antigen-presenting cells are stabilized by specific antigen recognition TCR+MHC-peptide: Increase the affinity of ICAM1 and LFA1 The association lasts for several days , during which time naïve T cell proliferates and its progeny associate with APC: proliferation and differentiation to armed T cells

27. Activation of naïve T cells required three signals delivered from APC CD28-B7 induce T cells express growth factor IL-2 and its high affinity receptor (CD25, IL2Ra)

28. Co-stimulatory molecules B7 molecules B7.1 (CD80) and B7,2 (CD86) Ig superfamily CD28: ligand of B7 CD28-B7 +TCR-Self/MHC CD40L (T cell surface) CD40L-CD40 (APC) B7 (APC) The principal co-stimulatory molecules expressed on antigen-presenting cells are B7 molecules, which bind the T-cell protein CD28 IL-2 and IL-2Ra increase Another costimulation molecules: T cells: 4-1BB (CD137) APC: 4-1BBL

29. Activated T cells synthesize the T cell growth factor interleukin-2 and its receptor High-affinity IL-2 receptors are three-chain structures that are produced only on activated T cells Resting T cells: bg, moderate affinity high IL-2 • Activated T cells: abg • High affinity • Low IL-2 CD25: a chain IL-2 are necessary for the T cell proliferation Anergic cells can not produce IL-2

30. Activated T cells secreted and response to IL-2

31. T-cell activation leads to the increased expression of CTLA-4, an inhibitory receptor for B7 molecules CTLA-4 (CD152) --CD28 related protein also bind to B7 --Expressed on activated T cells. --less than CD28 even in high peak, --In terms of the B7 avidity, CTLA is 20X higher than CD28 B7-CD28: positive signals B7-CTLA4: inhibitory signals CTLA-/-: proliferative massively, Lymphadenopathy, is important in lymphocyte homeostasis CD28: rest and activated T cells

32. T cell anergy The requirement for one cell to deliver both the antigen-specific signal and the co-stimulatory signal is crucial in preventing immune responses to self antigens MHC class I present endogenous peptide which is not eliminated in the thymus Why the retention of angeric T cells? Anergic cells can not produce IL-2

33. Armed effectors T cells can respond to their target cells without co- stimulation

34. Armed effector T cells changes the expression of several cell-surface molecules Armed effector : Loss of L-selectin results in ceasing to recirculate through lymph node Expression of VLA-4 allow the activated cells to bind to VCAM which is expressed at the sites of inflammation CD45RO: associate with TCR and CD4, more sensitive to peptide/MHC

35. Naïve CD8 T cells can be activated in different ways to become armed effector cells 1.Naive CD8 T cells can be activated directly by potent antigen-presenting cells Need more co-stimulatory molecules than Th Tc against Tumor

36. Some CD8 T-cell responses require CD4 T cells 2. Naïve CD8 T cells can be activated in the presence of Th. In these response CD8 and CD4 T cells must recognize related antigens on the surface of the same antigen presentation cells CD40-CD40L: Increase the co-stimulatory molecules on APC 4-1BBL:another co-stimulatory moleculesonly expressed on activated DC, macrophage and B cells Activated CD40 increase the co-stimulatory molecules expressed on APC

37. Inhibit T cell proliferation, IL10 and TGFb Nature T reg: CD4+CD25+, 10-15% Th3: Mucosa, IL-4, IL-10 and TGFb Tr1: culture in IL-10, TGFb Adaptive regulatory: TGFb inducted Foxp3, TGFb Various signal3 causes naïve CD4 T cells to acquire distinct effector function IL23

38. The different type of effector cells are specialized to deal with different types of pathogens Effectors Action depend on: The array of membrane, secreted protein, and mediator released upon receptor ligation The effector proteins focus on the target cell by mechanism that activated by recognition of antigen on the target cells Chemokines Prevent autoimmunity proinflammatory

39. T cell activation and Cell Mediated Effector Response • Entry of naïve T cells and APC cells into • peripheral Lymphoid organs 2. The production of armed effector T cells 3. General properties of armed effctor T ells. 4. T ell mediated cytotoxicity 5. Macrophage activation by armed CD4 Th1 cells

40. Interactions of T cells with their targets initially involve nonspecific adhesion molecules TCR+MHC-peptide; prolong the binding of target cells with effector cells Th bind to macrophage or B cells for long period ? Disengage from target cells.

41. Tight junctions are formed between armed effector T cells and their targets cSMAC pSMAC a B cell: a T cell SMAC: supramolecular adhesion complex The area of contact between an armed effector T cells and its contact forms an immunological synapse Control the delivery of effectors: 1.Stable binding, tight held, narrow space 2.Focus the delivery at the site of contact 3. Triggers the synthesis or release

42. The polarization of T cells during specific antigen recognition allows effector molecules to be focused on the antigen-bearing target cell Nonspecific adhesion binding TCR binding to target cells T cell become polarized : aligns the microtubule organization center (MTOC), sectory aparatus, Golgi Binding of the T-cell receptor complex direct release of effector molecules and focus them on the target cells

43. The different types of effector T cells produce distinct sets of effector molecules Fas ligand (FasL): Membrane associated TNF-related moleculesexpressed by cytotoxic T cells and some Th cells ,which kill the activated Fas bearing lymphocytes The effector functions of T cells are determined by the array of effector molecules that they produce

44. The nomenclature and functions of well-define T-cell cytokines I Most of the cytokines have local effects that syngergize with those of the membrane bound effector molecules Synthesis of IL-2,IL-4 and IFN-g is controlled and confined to target cells More distant effect: IL-13 and GM-CSF producing macrophage and granulocytes IL-5: eosinpophil IL-3 and GM-CSF: DC

45. The nomenclature and functions of well-defined T-cell cytokines II

46. The nomenclature and functions of well-defined T-cell cytokines III

47. Cytokine-mediated generation and cross regulation of Th subsets

48. Cytokines and their receptors can be grouped into a small number of structural families Cytokine receptors belong to families of receptor proteins, each with a distinctive structure Cytokines: Hematopoietin IFN TNF I: a: ligand specificity b or g: signal transduction TNF receptor: ligand: trimer, membrae bound

49. T cell activation and Cell Mediated Effector Response • Entry of naïve T cells and APC cells into • peripheral Lymphoid organs 2. The production of armed effector T cells 3. General properties of armed effctor T ells. 4. T ell mediated cytotoxicity 5. Macrophage activation by armed CD4 Th1 cells

50. Cytotoxic CD8 T cells can induce apoptosis in target cells Why cell mediated cytotoxicity ? Intracellular pathogen: Not accessible to Ab Eliminated by destruction or modification of infected cells Tc+target cells: Program to death within 5 minutes Death take hours to be evident ??? Apoptosis: Kill host cell , cytosolic pathogens Nonviral cytosolic path Why is apoptosis but not necrosis ????