Topics T cell mediated immunity Part II Effector

Topics • T cell mediated immunity Part II – Effector T cells – Binding and secretion of effector molecules – CD 8 T cell function – CD 4 T cell function – Cytokines – TH 1 effector functions 1/19/2022 MICR 415 / 515 / 682 1

Effector T cells 1/19/2022 MICR 415 / 515 / 682 2

• Adhesion molecules allow for longer cell-cell interaction • CD 4 cells bind to target cells for a long time • CD 8 T cells bind to targets cells for short periods, kills target cell, then detaches and binds to another cell 1/19/2022 MICR 415 / 515 / 682 3

– Binding leads to clustering of receptors – Polarization: 1. Reorganization of cortical actin cytoskeleton at site of contact 2. Reorientation of microtubule reorganizing center 3. Relocalization of Golgi apparatus 1/19/2022 x 4. Exocytosis at site of contact (tight space) – Detachment Fig 8. 28 MICR 415 / 515 / 682 4

Two types of effector molecules: 1. Cytotoxins 2. Cytokines Fig 8. 28 1/19/2022 MICR 415 / 515 / 682 5

Cytotoxins – Soluble secreted factors 1. perforin 2. granzyme – Membrane associated factors 1. Fas Ligand 1/19/2022 MICR 415 / 515 / 682 6

Cytokines • Small secreted soluble molecules that can change the behavior or properties of the cell itself or of another cell • Multiple effects in different types of cells • Synergism • Lymphocytes = lymphokines • T cell = Interleukines • Chemoattractants = chemokines • Studied by in vitro assays or gene disruption 1/19/2022 MICR 415 / 515 / 682 7

Types of effector T cells CTL Cytotoxic T cells CD 8 MHC I recognition Kill viral infected cells Kill Transformed cells Th 1 CD 4 MHC II recognition Activation of macrophages Th 2 CD 4 MHC II recognition Activation of B cells 1/19/2022 MICR 415 / 515 / 682 8

Effector Molecules 1/19/2022 MICR 415 / 515 / 682 9

CD 8 T cells 1/19/2022 MICR 415 / 515 / 682 10

The kiss of death 1/19/2022 MICR 415 / 515 / 682 11

CTL effector molecules • Perforin: forms a pore in membrane • Granzymes: Serine proteases, activate apoptosis • Fas ligand: activates apoptosis • IFN- : inhibits viral replication, up-regulate MHC I expression, activates macrophages • TNF- : synergizes with IFN- , induce apoptosis 1/19/2022 MICR 415 / 515 / 682 12

Cytotoxic T cells are selective 1/19/2022 MICR 415 / 515 / 682 13

CD 4 T cells TH 0 TH 1 1/19/2022 & TH 2 MICR 415 / 515 / 682 14

Differentiation of CD 4 cells • Initial response mounted by the innate non-specific immune response is important in this process 1. Cytokines elicited by infectious agents 2. Molecules used for costimulation 3. Nature of MHC: peptide ligand 1/19/2022 MICR 415 / 515 / 682 15

Main Th 1 cytokines • IL-2 (Th 0, Th 1, CTL) – Growth of T cells – Growth of NK cells • IFN- (Th 1, CTL) – Increase MHC I & II – Inhibits Th 2 cell growth – Activates macrophages – B cell differentiation, Ig. G 2 a synthesis – Activates NK cells Figure 8: 31, appendix 2 1/19/2022 MICR 415 / 515 / 682 16

Main Th 2 cytokines • IL-4 (Th 2) – – – B cell activation and growth Th 2 growth and survival Increase MHC II Ig. G 1, Ig. E Decreases macrophage activation • IL-5 (Th 2) – Ig. A – increase eosinophils • IL-10 (Th 2) – Increase MHC II – Inhibit Th 1 cell growth 1/19/2022 MICR 415 / 515 / 682 17

other cytokines • IL-3 (Th 1, Th 2, CTL) – Stimulates hematopoiesis • TNF- (Th 1, some Th 2, CTL) – Activates macrophages (synergy with IFN- ) – production of NO • GM-CSF (Th 1, Th 2, CTL) – Increase granulocyte production – Increase macrophage and dendritic cell production 1/19/2022 MICR 415 / 515 / 682 18

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Consequences of Th 1 or Th 2 Leishmania sp Th 1 Th 2 Anti-IL-4 Resistant Susceptible Th 2 Th 1 Susceptible Resistant 1/19/2022 MICR 415 / 515 / 682 22

Macrophage activation • Requires 2 signals: • • • IFN -gamma CD 40 or membrane bound TNF alpha or beta • Stimulation via TCR triggers novo protein synthesis • Proteins are delivered to the site of contact by vesicles • Signals are delivered directly to that macrophage 1/19/2022 MICR 415 / 515 / 682 23

Activated macrophage 1. Increase fusion of lysosomes and phagosomes to form phagolysosomes 2. Increase oxygen radicals and Nitric Oxide production 3. Increase expression of B 7, CD 40, MHC II & TNF receptors 4. Production of IL-12 (stimulates Th 1 cells) 5. Recruitment of other cells 6. More effective killing 7. Better APC 1/19/2022 MICR 415 / 515 / 682 24

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