© Garland Science 2009

CChapter 8:hapter 8:

T Cell-Mediated T Cell-Mediated ImmunityImmunity

Activation of naive T cells on encounter with antigen

• T cell activation (priming)

• T cell effector functions

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

Activation of naive T cells on encounter with antigen

• Immature dendritic cells capture antigen and migrate to secondary lymphoid tissue (T cell regions of the cortex) where they become mature/activated dendritic cells

• Macrophages (role in defense and repair of damaged tissue) are resident in tissues

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

Dendritic cells carry antigens from sites of infection to secondary lymphoid tissues

Dendritic cells are adept and versatile at processing antigens from pathogens

yellow = endocytic vesiclesred = lysosomal proteingreen= MHC class II

activation induces CCR7, the receptor for CCL21, whichchemokine is madein secondary lymphoid tissue(results in migration to lymph nodeand stops further processing as a consequence dendritic cellfocusses on T cell activation)

Activation of naive T cells on encounter with antigen

• Antigen capture by dendritic cells takes place by a) receptor mediated endocytosis

b) macropinocytosis (ingestion of large amounts of extracellular fluid)

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

Dendritic cells use various pathways to process and present protein antigens

Activation of naive T cells on encounter with antigen

• Naive T cells first encounter antigen presented by dendritic cells in secondary lymphoid tissues

• dendritic cells enter via afferent lymp (drains from the site of infection

• Naive T cells enter the lymph node by

a) squeezing through blood capillaries (high endothelial venules) and enter the cortecal region

b) through the lymph from an upstream lymp node (efferent lymp)

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

Naive T cells (blue and green

dendritic/macrophagesniffing

T cell that do not encounter their specific antigenleave (green) whereas the ones that do, are activated, proliferate and differentiate into effector cells

Naive T cells encounterantigen in the secondarylymphoid organs

How the lymph network works

In any given infectiononly 1 in 104 to 1 in 106 of the total pool ofcirculating T cells is activated.

Homing of naive T cells

to secondary lymphoid

tissues is determined

by chemokines and

cell-adhesion molecules

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

Naive T and B cells circulate in the blood and enter lymph nodes by crossing high endothelial venules

chemokine = CCL21 and 19 which binds to CCR7 receptor on Naive T cell

More about lymphocyte adhesion to professional antigen-presenting cells (APC)

DC-SIGN a lectin unique to activated DC

Transient adhesive interactions between T cells and DC are stablized by specific Ag-recognition

Activation of naive T cells requires a co-stimulatory signal

delivered by a professional antigen-presenting cell

signal 1 induces clonal expansion but only when signal 2 is delivered

B7.1 and 7.2 are known ascostimulatory molecules

CTLA4 is expressed onlyon activated T cells,is similar to CD28but binds much stronger toits ligand B7 and works asan atagonist

Activation of naive T cells on encounter with antigen

• There is a concentraton gradient of (sphingosine 1-phosfate (S1P) from the lymp/blood to the secondary lymphoid tissues

• T cells activated by Ag suppress the expression of S1P receptors for several days (makes them stay in the lymph node while they differentiate into effector cells). Later they are drawn away by the gradient of S1P

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

Secondary lymphoid tissues contain three kinds of professional antigen-presenting cells which populate distinct areas

Microbial substances induce co-stimulatory activity in macrophages

The immunological synaps (T cell synaps)

ITAM = immune receptor tyrosine-based motif

A simple outline of the intracellular signalling pathway initiated by the T cell receptor, CD4 and CD28

IL2/4 production

Activated T cells secreteand respond to IL-2 (part I)

Activated T cells secreteand respond to IL-2 (part I)

cyclosporine-A,tacrolimus (FK506),and rapamycine are immunosuppressive drugs that inhibit IL-2production or signallingfrom the IL-2 receptor

Ag recognition by a naive T cell in the absence of co-stimulation leads to anergy

On activation, CD4 T cells acquire distinctive helper functions

Different cytokine profiles drive the differentiation of CD4 positiveT cells that produce different cytokines and possess distinct functions

cell mediated immunity (TH1)

humoral immunity(TH2)

Polarization of immune responses in different clinical forms of leprosy

TH1 TH2

Naive CD8 T cells are activated to become cytotoxic effector cells in several different ways

Effector T-cell responses to infection do not depend on co-stimulatory signals

Activation of T cells changes the expression of several cell-surface molecules

VCAM-1 AD AD AD alt. spl improves Ag pres.

Integrin VLA-4 enables effector T cells to home to inflamed tissue

Many cytokine receptors signal through a pathway in which receptor-associated kinases activate transcription factors directly

JAK = Janus kinases STAT = signal transducers and activators of transcription

The three types of effector T cell produce distinct sets of effector molecules

Kiss of death

LG lytic granulesMTOC microtubuleorganizing center

Cytotoxic CD8 T cells are selective and serial killers of

target cells at sites of infection

Cytotoxic T cells kill their target cells by inducing apoptosis

or programmed cell death

Two pathways; 1 by granzymes, perforin and granulysin 2 Fas ligand

Lymphadenopathy in autoimmune lymphoproliferative syndrome (APLS) in an indvidual who lacks FAS molecules

TH1 CD4 cells activate macrophages to become highly microbicidal

conjugate pair, activation requires two signals

TH1 cells coordinate the host response to pathogens that live in macrophages

Granuloma’s form when an intracellular pathogen or its constituents resist elimination (MT)

The properties and functions of effector T cells

• CD4 TH2 cells activate only those B cells that recognize the same antigen as they do

• Regulatory CD4 T cells (Tregs) limit the activities of effector CD4 and CD8 T cells

Chapter 8

© Garland Science 2009

T Cell-Mediated Immunity

CD4 TH2 cells activate only those B cells that recognize the same antigen as they do

molecular components recognized both by B and T cells make effective vaccines

The adaptive T cell response has two distinct stages