Part IV The adaptive immune response Chapter 9 T Cell-Mediated Immunity

APC 2

Periphery Naïve Effector Activated Ag-specific T cell response Each with different Ag specificity Naïve Low frequency Periphery Ag-specific T cell response Effector Clonal expansion Ag Activated Ag-specific T

Effector T cells in CMI and humoral immunity Effector T subsets

CD4 T cell differentiation Treg Th17 Treg Promote local inflammation CMI: CD8 T Humoral response

From inflammatory site Entry of APC and naïve T cells into peripheral lymphoid organs Priming of naïve T cells by DC Effector T cell response

Professional APC 7

DC subsets cDC (CD11chi) pDC Viral infection

Entry of DC

DC maturation / differentiation / migration Licensing DC maturation / differentiation / migration

Lymphocyte entry into LN from blood HEV Adhesion molecules Adhesion molecules

Lymphocyte entry into LN from blood CCR7 CCL21 T zone: CCL21, CCL19 SLC: Secondary lymphoid tissue chemokine

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

Naïve T cell activation in peripheral lymphoid organs Naïve Activated Ag specificity Naïve T cell activation in peripheral lymphoid organs Naïve Activated Effector

Periphery Naïve Effector Activated Ag-specific T cell response Each with different Ag specificity Naïve Low frequency Circulation Periphery Ag-specific T cell response Effector Clonal expansion Ag Activated Lymph nodes Ag-specific T

Activation of LFA1 Signal 1 16

Three signals in naïve T cell activation Signal 2: proliferation

Amount of Ag expression T cell activation Amount of Ag expression T-APC Avidity Supramolecular activation compolex (SMAC) 18

Signal 1+2 CD28-dependent clonal expansion of CD4 T cells IL2 CD25

Signal 1+2 IL2 autocrine for CD4 T clonal expansion

Naïve T cell activation in peripheral lymphoid organs Naïve Ag specificity Naïve T cell activation in peripheral lymphoid organs Naïve

Activation of LFA1 Signal 1 22

Regulation of signal 2

Signal 1 alone in LN? Clonal deletion Clonal anergy Self tolerance

Type of Ag-specific effector

Signal 3: differentiation Transcription factor Adaptive Treg

CD4 T-dependent CD8 T cell activation IL2 DC (APC) activation CD40L-CD40 CD8 T Colgate Immunology (and Virology) Blog

Ag

Ag capture and preservation by subcapsular sinus macrophage CXCR5 Low phagocytosis CXCL13 CCL21 Ag –nonspecific B cells

Ag-specific stimulation B-T cell interaction CCR7 induction B cell as APC

CD4 T activation Within LN Egress

Egress S1P R Plasma: Sphingosine 1-phosphate (S1P) 32

Sphingosine-1-phosphate (S1P) The AOCS Lipid Library An important cellular metabolite in animal cells A ceramide-derived phospholipid

Blood mononuclear cells, Neutrophils, Erythrocytes. S1P producer: Blood mononuclear cells, Neutrophils, Erythrocytes. Efficiently phosphorylate exogenously added sphingosine and discharge S1P into the medium, which suggests a general contribution of hematopoietic cells in maintaining plasma S1P levels. It is relatively insoluble in aqueous solution. Most of the plasma S1P is bound to carriers such as albumin.

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

Homing Migration of effector T cells to inflammatory site

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

Homing Addressin Guiding lymphocytes to tissues Ig domain Vascular addressin (VA) 38

Ag-specific recognition of CD8 T cells

Requirement of signal 2 for effector function? No signal 2 is required

Microtubule-organizing center Cytotoxic mechanisms of CD8 T cells Microtubule-organizing center Cytotoxic granules

Membrane effector molecule CTL

Effector molecules Membrane molecules Soluble mediators

APC Professional APC

Macrophage activation & CD4 T activation

Macrophages activation by Th1

Reciprocal activation

Th1 effectors tissue

Effector T cells recruitment 49

Lymphocyte activation Apoptosis of effectors Signal 1-3 Lymphocyte activation Innate immunity Effector response Apoptosis of effectors