Immunology. T-Lymphocytes. 16. Oktober 2014, Ruhr-Universität Bochum Karin Peters,

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1 Immunology T-Lymphocytes 16. Oktober 2014, Ruhr-Universität Bochum Karin Peters,

2 The role of T-effector cells in the immune response against microbes cellular immunity humoral immunity Pathogens Vacciniavirus, Influenza virus, Rabies virus Mycobacterium tuberculosis, Mycobacterium leprae, Clostridium tetani, Staphylococcus aureus, Streptococcus pneumoniae localization Cytosol Phagosomes of macrophages Extracellular T-lymphocytes Cytotoxic CD8 + T-lymphocyte T H 1 CD4 + T-lymphocyte T H 2 CD4 + T-lymphocyte Recognized antigen Peptide: MHCclass-I on infected cell Peptide: MHC-class-II on infected macrophages Peptide: MHC-class-II on antigen specific B- lymphocytes Effector mechanism Killing of infected cells Activation of macrophages Induction of antibody production of B-cells

3 All T-lymphocytes are derived from hematopoethic stem cells from the bone marrow Activated Lymphocyte in blood

4 Life cycle of T-lymphocytes

5 Development of T-lymphocytes in the thymus

6 Rearrangement of TCR genes in the genome I Figure 7-21 part 1 of 3

7 Rearrangement of TCR genes in the genome II Figure 7-21 part 2 of 3

8 Rearrangement of genes in the genome III

9 Diversity of T-cell receptors β-chain α-chain V-segments D-segments 2 0 J-segments N- and P-nucleotids 2 1 Number of theoritical rearrangements Combinatorial diversity 5,7 x 10 6 Total diversity Which strategies exist to avoid recognition of self-antigens?

10 Selection of T-lymphocytes in the Thymus Positive selection on ability of binding to MHCI and MHCII molecules Cells with no affinity to MHC die by apoptosis Negative selection of T-lymphocytes binding to self antigens with high affinity Cells binding to self antigens die by apoptosis

11 Presentation of antigen by dendritic cells Immature DCs are specialized in engulfment of antigens and present peptides of the digested proteins on MHC molecules

12 Characteristics of MHC molecules MHC class I MHC class II Expression by cell type all nucleated cells on antigen presenting cells Interaction with T-cell subsets CD8 cytotoxic T-cells CD4 T-helper cell Genloci HLA-A, B and C HLA-DR, DP and DQ Molecular structure α-chain associated with β2-microglobulin α-chain associated with β chain Peptides presented 8-10 amino acids larger than 13AA Intracellular Location Endoplasmatic Reticulum Endosomes

13 On MHC class I peptides were presented that are derived from intracellularly synthesized proteins Virus infecting cell

14 Presentation of peptides on MHC I to T- Lymphocytes Cell membrane Peptide Cell membrane

15 On MHC class II peptides were presented that are derived from extracellular sources APC Extracellular Proteins engulfed by antigen Presenting cell

16 Presentation of peptides on MHC II to T- Lymphocytes Cell membrane Peptide Cell membrane

17 Anergy: Recognition of antigen without costimulation

18 Interaction of Co-stimulatory molecule CD80/86 with CD28 is essential for optimal Interaction activation between of LFA-1 effector and T-cells ICAM-1 leads to stabilization of interaction between T-cells and Antigen Presenting Cell (APC) T-helper-cell Cytotoxic T-cell APC APC Interaction between CD4 and MHCII or CD8 and MHCI amplifies the signal given by interaction of the MHC-Peptide complex with the TCR

19 Intracellular signal transduction

20 Figure 6-5 Ca 2+ activates Calcineurin which in turn activates NFAT PKC activates NFκB

21 Activation of T-lymphocytes induces production of IL-2 Figure 8-20

22 Effector mechanisms of activated T-lymphocytes

23 Cytotoxic T-lymphocytes kill target cells by induction of apoptosis Figure 8-34

24 The different stages of the activation of T-lymphocytes naive CD4-T-Cells Activated proliferating T-Cell Activated T-Cell not determined (T H 0) T H 1-Cell T H 2-Cell Activation of macrophages; B-cells produce antibodies of the isotype IgG1 Activation of B-cells they produce antibodies of IgE, IgG4; activation of eosinophilic granulocytes aus: Immunologie, Janeway et al.

25 Example for the importance of the decision whether Th1 or Th2 response is induced for the outcome of disease Leprosy Mycobacterium leprae-infection Tuberculoid Leprosy Lepromatous Leprosy M leprae resides in vesicles of macrophages; macrophages were activated by Th1-cells leading to control of microbial burden; only few bacteria detectable in blood, low antibody titre; Inflammation of skin and Nerves but patients survive! Uncontrolled growth of M. leprae in macrophages; Th2-cells do not activate macrophages; however they induce production of non protective antibodies; disease resulting in massive destruction of tissue often resulting in fatal outcome

26 Differentiation of Th1 or Th2 lymphocytes Th2 Th0 Th1

27 Th2 IL-4 Th0 Th1 IFN-γ

28 Mast/Baso IL-4 Th2 IL-4 + Th0 IL-12 + Th1 IFN-γ DC

29 Mast/Baso IL-4 Th2 IL Th0 - IL-12 + Th1 IFN-γ DC

30 The immune response to cells infected with bacteria is coordinated by Th1 Lymphocytes activated T H 1-cell IFN-γ Fas-Ligand oder TNF-β IL-2 IL-3 + GM- CSF TNF-α Activation of macrophages leading fusion of lysosomes and phagosomes Killing of infected cells by apoptosis Autocrine mechanism proliferation of T-cells Generation of macrophages and DCs in bone marrow Activation of endothelium to attract macrophages

31 T H 2-cells are important for amplification of B-cell responses and involved in defense against parasites activated T H 2-cell IL-2 IL-4 IL-5 IL-10 IL-13 Autocrine stimulation of T-cell proliferation, paracrine stimulation of B- lymphocytes Activation of B-lymphocytes Isotype switch to IgG4 and IgE, triggering of Th2 immunity while suppression of Th1 immunity Proliferation and activation of eosinophilic granulocytes Regulation of immune response Activation and proliferation of B-lymphocytes

32 But in the last years several new subpopulations of T-helper cells were described.

33 O Shea&Paul SCIENCE 327:1098

34 Th17 cells are important for elimination of fungal infections IL-6 TGFβ IL-23 + Th0 Th17 IL-17 Fibroblast IL17R IL-6 IL-8 Neutrophilic Granulocytes

35 Regulatory T-helper cells are important for down regulation of the immune response IL-10 + IL-10 Th0 T reg TGF-β Inflammation T-cells

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