Page 263 - Clinical Immunology_ Principles and Practice ( PDFDrive )

244 PArT TwO Host Defense Mechanisms and Inflammation

ACTION OF INHIBITORY RECEPTORS loss of receptor expression deprives the cell of survival signals,
resulting in AICD. Similarly, loss of IL-7 or IL-7 receptor results
T cells express several Ig family transmembrane proteins contain- in increased apoptosis among naive and memory T-cell popula-
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ing immune tyrosine inhibitory motifs (ITIMs). Two of these, tions. As discussed in Chapter 13, cell death by growth factor
CTLA4 and PD-1, play important roles in terminating T-cell withdrawal results from activation of the mitochondrial pathway
responses in vivo. The first, CTLA4, is expressed by T cells fol- of apoptosis.
lowing activation and regulates T-cell activity in two ways: first, Cytokines can suppress T-cell responses. This function of
CTLA4 binds to B7 with high affinity and competes with CD28 cytokines is exemplified by IL-10, IL-27, TGF-β, and TNF-α.
costimulation. Second, CTLA4 inhibits proximal TCR signaling IL-10 is produced by adaptive Tregs and Tr1 cells, as well as B
by recruiting the phosphatases SHP-2 and PP2A. Mice deficient cells, monocytes, and macrophages. IL-10 suppresses inflammation
in CTLA4 develop a severe CD28-dependent lymphoproliferative by inhibiting macrophage activation, downregulating chemokine
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disease, tissue infiltration, and early death. PD-1 interacts with production, and suppressing costimulatory molecule expression
two ligands, PD-L1 and PD-L2, which are differentially expressed by APCs. IL-10–deficient mice develop inflammatory bowel
in immune and peripheral tissues. PD-1 engagement limits disease caused by dysregulated Th1 responses. Mice genetically
proximal TCR signals by recruiting SHP-2, thereby suppressing deficient for the IL-27 receptor develop exaggerated CD4 T-cell
activation, cytokine production, and proliferation. Loss of PD-1 responses and inflammatory diseases. These effects of IL-27 can
has been associated with autoimmune cardiomyopathy, arthritis, be attributed to its role in suppressing Th1 responses and CD4
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and a lupus-like glomerulonephritis disease. 35 T cell proliferation. TGF-β 1 is another antiinflammatory cytokine
that is produced by subsets of Tregs and a variety of other cell
CYTOKINE-MEDIATED INHIBITION types throughout the body. Unlike IL-10, which targets APCs,
TGF-β 1 directly inhibits T-cell proliferation and Th1 differentia-
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Cytokines function to terminate immune responses in three basic tion. Mice deficient in TGF-β 1 have multitissue infiltration by
methods: (i) by loss or withdrawal of growth factors, (ii) by activated lymphocytes and macrophages. TNF-α is well character-
inducing cell death, and (iii) by direct antiinflammatory properties ized as possessing proapoptotic function. TNFR1 possesses a
(Chapter 9). IL-2 functions as a growth factor in early immune death domain, and binding of TNF-α results in the activation
responses. Loss of IL-2 signals through decreased production or of the caspase pathway and apoptosis.

Process Targets Effects
Activation Costimulatory Block T-cell and APC
molecules activation
Intracellular Block proliferation
signaling
molecules Limit cytokine production
DC
Limit differentiation
Tcell

Migration Chemokines Prevent recruitment of
T cells and effector cells
into tissues
Blood Integrins Prevent effector function
vessel Prevent extravasation

Cytokine production
Inflammatory Dampen effector cell
T reg cytokines activation and function
Enhance effector function
B cell
Regulatory Prevent recruitment of T cells
T h2 B B cytokines and effector cells into tissues

IL-4
FIG 16.5 Therapeutic Regulation of Inflammation. Several techniques have been employed
to reduce T-cell responses in cases of inflammation. Among these are inhibiting T-cell activation
and differentiation by blocking costimulatory interactions with antigen-presenting cells (APCs)
(top); inhibiting T-cell and effector-cell trafficking by blocking molecules required for chemotaxis
(middle); and limiting the effect of T-helper responses by decreasing the availability of inflammatory
cytokines (bottom).