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© Garland Science 2009
CChapter 8:hapter 8:
T Cell-Mediated T Cell-Mediated ImmunityImmunity
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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
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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
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Dendritic cells carry antigens from sites of infection to secondary lymphoid tissues
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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)
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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
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Dendritic cells use various pathways to process and present protein antigens
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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
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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
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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.
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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
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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
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More about lymphocyte adhesion to professional antigen-presenting cells (APC)
DC-SIGN a lectin unique to activated DC
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Transient adhesive interactions between T cells and DC are stablized by specific Ag-recognition
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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
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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
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Secondary lymphoid tissues contain three kinds of professional antigen-presenting cells which populate distinct areas
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Microbial substances induce co-stimulatory activity in macrophages
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The immunological synaps (T cell synaps)
ITAM = immune receptor tyrosine-based motif
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A simple outline of the intracellular signalling pathway initiated by the T cell receptor, CD4 and CD28
IL2/4 production
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Activated T cells secreteand respond to IL-2 (part I)
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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
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Ag recognition by a naive T cell in the absence of co-stimulation leads to anergy
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On activation, CD4 T cells acquire distinctive helper functions
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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)
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Polarization of immune responses in different clinical forms of leprosy
TH1 TH2
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Naive CD8 T cells are activated to become cytotoxic effector cells in several different ways
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Effector T-cell responses to infection do not depend on co-stimulatory signals
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Activation of T cells changes the expression of several cell-surface molecules
VCAM-1 AD AD AD alt. spl improves Ag pres.
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Integrin VLA-4 enables effector T cells to home to inflamed tissue
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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
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The three types of effector T cell produce distinct sets of effector molecules
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Kiss of death
LG lytic granulesMTOC microtubuleorganizing center
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Cytotoxic CD8 T cells are selective and serial killers of
target cells at sites of infection
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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
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Lymphadenopathy in autoimmune lymphoproliferative syndrome (APLS) in an indvidual who lacks FAS molecules
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TH1 CD4 cells activate macrophages to become highly microbicidal
conjugate pair, activation requires two signals
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TH1 cells coordinate the host response to pathogens that live in macrophages
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Granuloma’s form when an intracellular pathogen or its constituents resist elimination (MT)
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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
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CD4 TH2 cells activate only those B cells that recognize the same antigen as they do
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molecular components recognized both by B and T cells make effective vaccines
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The adaptive T cell response has two distinct stages