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T cell-mediated immunity
Chapter 8
Objectives
• Describe the protein-protein interactions necessary for
naïve T cell activation to occur
• Illustrate or describe the changes that occur in a
dendritic cell upon activation
• Explain the basic mechanisms through which cytotoxic T
cells, TH1 cells, and TH2 cells function
• Briefly describe the functions of regulatory T cells
• Predict appropriate target molecules for suppression of
T cell function
T cell-mediated immunity
Mature naïve T cell
(non self-reactive,
MHC-restricted)
Activation (stimulated by
binding to specific antigen
presented by APC)
Clonal expansion and
differentiation into armed
effector T cells (CTL, TH1, TH2)
Antigen presentation is required for T
cell activation
• “Professional” APCs are highly effective at
activating mature naïve T cells
>
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Dendritic cell
Macrophage
B cell
Professional APCs
MHCII
Lysosomal protein
T cells that become activated
remain in the lymph node
T cell activation occurs in peripheral
lymphoid tissues
• Mature naïve T cells leave
the blood and enter the Tcell zone of lymph nodes (or
peripheral lymphoid tissues)
– Mediated by proteinprotein interactions
between the T cell and
the endothelial cell
T cell : APC interactions
Naïve T cells require two signals
for activation
Costimulation
Costimulation
Costimulation
• CTLA4 is expressed on T cells after they
become activated
• Signaling through CTLA4 sends an “off
signal” to the T cell
• CTLA4 knockout mice have been created
• What would you expect the phenotype of
these mice to be?
Costimulation requirement helps
prevent autoimmune responses
Activated APCs express
costimulatory molecules
• Pathogens activate
APCs by inducing high
expression of
costimulatory
molecules
– TLR signaling
B7 and MHC II expression on splenic dendritic
cells from mice injected with LPS
# cells
Control
(ip PBS)
ip LPS
iv LPS
# cells
B7
MHCII
Adjuvants induce costimulatory
molecule expression on APCs
Cellular events triggered by activation
• Expression of highaffinity IL-2 receptor
(CD25)
• Secretion of IL-2
• Proliferation (clonal
expansion)
• Change in CAMs ( Lselectin)
• Differentiation into
armed effector T
cells
– No costimulation
required
Armed effector T cells
Armed effector T cells form stable
interactions with target cells
Effector molecules produced by
T cell subsets
Cytotoxic T lymphocytes (CTL,
TC, CD8+ T cells)
Cytotoxic T lymphocytes
Cytotoxic T lymphocytes
•Cytotoxic T lymphocytes express cytotoxins:
–Perforin forms pores in target cell membranes
–Granzymes are proteases that cleave caspase-3
•Also express Fas ligand, IFN-, TNF
Cytotoxic T lymphocytes
•Effects of CTLs
are highly
specific
TH1 cells
TH1 cells
Granulomas form when intracellular
pathogens are not eliminated
What determines whether helper
T cells become TH1 or TH2 cells?
• Cytokines expressed by APCs and phagocytes
determines differentiation fate of helper T
cells
• TH1 cells suppress differentiation of TH2
cells, and vice versa
Regulatory T cells
• Regulatory T cells suppress the activity of
other classes of T cells
– Evidence for multiple subsets of regulatory
T cells
• CD4+/CD25+ T cells
• TR1
• TH3
• Regulatory CD8+ cells
– Some secrete IL-10 and/or TGF-
– Some require contact with other T cells to
have effects
– Antigen-specific or “bystander” suppression
Regulatory T cells can suppress
inflammation
Inflamed colon in mouse model
of colonic inflammation
Same mouse model given CD4+
CD25+ regulatory T cells by
IV transfer
Read, Malmstrom, & Powrie. Journal of Experimental Medicine 192:295-302, 2000.
Discussion questions
• What effect on T cell-mediated immunity would
each have?
– A blocking antibody to IL-2 or to the highaffinity IL-2 receptor
– A blocking antibody to TNF-
– Soluble CTLA-4 (mimics CTLA-4 activity)
– A blocking antibody to IFN-
– Collecting naïve T cells from a patient,
stimulating them to become antigen-specific
CTL against a tumor antigen, and injecting
back into the patient