1 Circulating T cells Ag in the Inflammatory tissue Ch 9 T Cell-Mediated Immunity Ag-specific T cell response

Entry of APC (DC) and naïve T cells into peripheral lymphoid organs Priming of naïve T cells by DC Clonal expansion & differentiation Signal 1, 2, 3 Egress 2

Entry of DC into draining LN 3 Inflammation Immature DC: Ag uptake CCR7 Ag presentation (signal 1) B7 (signal 2) Mature DC (T cell zone) CCL21

Naïve T cell activation in peripheral lymphoid organs 4 Naïve Activated Effector 500 T cells/hr for 1 DC Naïve T: CCR7

T-APC interaction: activation of LFA1 Signal 1 5 Ag specificity

Three signals in naïve T cell priming Signal 2: proliferation 6

IL2 autocrine Signal CD28-dependent clonal expansion of CD4 T cells

Signal 3: differentiation Adaptive Treg 8 Transcription factor Effector T subsets Induced Treg

9 Colgate Immunology (and Virology) Blog CD40L-CD40 2. IL2 CD4 Th1-dependent CD8 T cell activation CD8 T 1. DC (APC) activation

DC CD8T APC 10

TRA: Tissue restricted antigen mTEC: AIRE transcription factor 2011, 32: 188 Thymic negative selection : Self tolerance

Effector T cell response CD8 T cytotoxic response CD4 T effector & Macrophage activation Homing 12 Entry of APC and naïve T cells into peripheral lymphoid organs Priming of naïve T cells by DC

Homing Effector response CD4 Th1/ Th2 CD8 Tc B cells 13

Where to go ?

CD4 T activation Within LN 15

Ig domain Addressin Guiding lymphocytes to tissues Homing Vascular addressin (VA) 16

Ag-specific recognition of CD8 T cells 17

Microtubule-organizing center Cytotoxic mechanisms of CD8 T cells (NK) Membrane effector molecule CTL Cytotoxic granules 18

Membrane molecules Effector molecules Soluble mediators 19

20 APC Inflammatory site

Macrophage activation by Th1 Reciprocal activation 21

Th1 coordinates a macrophage response 22 Collaboration of adaptive and innate immunity tissue Systemic

The course of immune response to infection Immunological memory Ch 11 23

Innate immunity Humoral immunity CMI Sequential activation and regulation of T cell subsets 24

Amplifier of acute inflammation (local site, BM) 25

T H 17 Neutrophils Activation of macrophages Antimicrobial peptides Ubiquitous expression of IL17R on tissue cells: fibroblasts, epithelial cells, keratinocytes, etc. Cytokines: G-CSF, GM-CSF No IL4, IFNg, IL12) Chemokines: CXCL8, CXCL2 Proinflammatory cytokine Antimicrobial peptidesPhagocytosis Inflammed site Signal

Adaptive Treg T H 17 Rapid response to infection Preventing anti-self response Inhibition of proliferation & differentiation T H 17 27

28 In the later stages of infection Polarization IL12 – Th1IL4 – Th2 Intracellular infectionExtracellular infection

Regulation among CD4 T subsets Cytokine pattern of the dominant response Inhibition of early Th17 response 29 IL4

Th1 30

Th1 CMI Intracellular infection: Virus Intracellular bacteria Protozoa 31

Th2 Humoral response Mast cells Extracellular infection: Helminths Parasites Protozoa Bacteria Neutralizing Ab IL10 Early IL4 & Th2 polarization 32

Natural/adaptive Treg

Sequential activation and regulation of T cell subsets Survival and sequential activation of B cell subsets T/B cell activation & differentiation 34 Barrier immunity

Professional APC 35

Induction of antibody response in LN (Th2) B cell response B cell as APC Ag-specific 5 days Isotype switching Somatic hypermutation 36

Ab response are sustained in medullary cords and BM In situ 2-3 days, 6-7 cell divisions Plasma cells Life span: 2-4 days Germinal center BM Plasmablasts Life span: months - years Plasma cells 37

Adhesion molecules Homing R / addressin Chemokine & R Migration of immune cells 38 Sequential activation and regulation

CD5 B cells 39

CD5 B cells 40

Early blocking Reinfection Effector response 41

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The course of immune response to infection Immunological memory 44

Two types of memory T cells Central memory T Effector memory T 45

Maintenance of memory T cells TCR, IL7, IL15 46 Homeostasis

The role of IL7 in memory response 47

CD4 T-dependent CD8 T cell memory response Promote efficient effector activity Maintain memory T cell numbers 48

Memory T cells Balance of cell proliferation and death 49 Long-lived

Memory B cell response 50 Somatic hypermutation Isotype switching

51 Barrier immunity

Regulation of signal 2 53

Effector T cells recruitment Apoptosis of effectors 54

Continuous regulation of the expansion and effector activity in inflammatory sites 55

Protective immunity & time Apoptosis of effectors Long-lived 56

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Stages of infection and immune response Local inflammation Macrophage activation Activation of APC Activation of lymphocytes Homing of effectors Endothelial cells Collaboration with innate and tissue cells Endothelial cells 58