Page 25 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 1 The Human Immune Response 11

Signal transduction through the antigen receptor is a complex in regulation of Ig isotype switching. And IL-4, although known
process involving interactions between the specific receptor and primarily as a B-cell growth and differentiation factor, can also
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molecules coexpressed in the cell membrane. For B cells, this stimulate proliferation of T cells.
is a heterodimer, Igα/Igβ; and for T cells it is a macromolecular A distinct subset of cytokines is a large group of highly
complex, CD3, usually comprising γ, δ, εε and ς chains. conserved cytokine-like molecules, smaller than typical cytokines
Within the cell membrane, antigen receptor stimulation (~7–12 kilodaltons [kDa]), termed chemotactic cytokines, or
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induces phosphorylation of Igα/Igβ or CD3 and hydrolysis chemokines (Chapter 10). Chemokines are classified on the basis
of phosphatidylinositol 4,5-bisphosphate by phospholipase C, of the number and spacing of specific cysteine residues. They
leading to generation of diacylglycerol (DAG) and inositol regulate and coordinate trafficking and activation of leukocytes,
1,4,5-trisphosphate (IP 3 ). As a consequence of signal transduction functioning importantly in host defenses, and also broadly in a
and secondarily of DAG and IP 3 generation, tyrosine and serine/ variety of nonimmunological processes, including organ develop-
threonine protein kinases are activated. In turn, these kinases ment and angiogenesis. They are characterized by binding to
catalyze phosphorylation of a number of signal transducing seven-transmembrane-domain G protein–coupled receptors. Of
proteins, leading to activation of cytoplasmic transcription factors particular interest to clinical immunologists, the chemokine
NF-AT in T cells and NF-κB in both T cells and B cells. These receptors CCR5 and CXCR4 together with CD4 are utilized by
transcription factors then translocate to the nucleus, where they human immunodeficiency virus (HIV) as coreceptors to gain
bind to 5’ regulatory regions of genes that are critical to general- entry into target cells. 40
ized lymphocyte activation 37,38 (Chapter 12). Cytokines produced by activated T cells can downregulate as
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well as initiate or amplify immune responses. Downregulating
CELL-MEDIATED IMMUNE RESPONSES cytokines include IL-10 (produced by both T cells and B cells)
and transforming growth factor-β (TGF-β). The functions of
T-Cell Subsets IL-10 in vivo are thought to include both suppression of proin-
T lymphocytes expressing an αβ TCR can be divided into two flammatory cytokine production and enhancement of IgM and
major subpopulations based on the class of MHC molecule that IgA synthesis. TGF-β, produced by virtually all cells, expresses
their TCR recognizes and the consequent expression of one of a broad array of biological activities, including promotion of
a pair of TCR accessory molecules, CD4 or CD8 (Chapters 4, wound healing and suppression of both humoral and cell-
8). Binding of CD4 to class II MHC molecules or CD8 to class mediated immune responses.
I MHC molecules on APCs contributes to the overall strength In addition to their central role in initiation and regulation
of intercellular molecular interactions. The ratio of CD4 to CD8 of immune responses, CD4 T cells are important effectors of
cells in peripheral blood is usually about 2 : 1. cell-mediated immunity (Chapter 16). Through the elaboration
of inflammatory cytokines, particularly IFN-γ, they are essential
CD4 T Cells, Cytokines, and Chemokines contributors to the generation of chronic inflammation, character-
The activities of CD4 T lymphocytes, commonly referred to as ized histologically by mononuclear cell infiltrates, where their
T helper (Th) cells, are mediated predominantly through the principal role is thought to be the activation of macrophages.
secretion of cytokines (Chapter 9). Cytokine activity can include Additionally, in some circumstances CD4 T cells can function
autostimulation (autocrine function) if the cell producing the as cytotoxic effectors, either directly as CTLs (in which case the
cytokine also expresses a surface receptor for it, or stimulation killing is “restricted” for recognition of antigen-bound self-MHC
of other cells in the microenvironment of the cytokine-secreting class II) or through the elaboration of cytotoxic cytokines, such
cell (paracrine function) including B cells, APCs, and other T as lymphotoxin and TNF-α.
cells. Although it is now recognized that their biological effects A third subset of Th cells, designated Th17, has been recognized
are broader than implied by their name, many of the principal more recently. With differentiation driven particularly by TGF-β
cytokines active in the immune system are known as interleukins and IL-23 and characterized by the production of the proinflam-
(ILs), implying that they are produced by a leukocyte to act on matory cytokine IL-17, Th17 cells are important in the induction
other leukocytes. and exacerbation of autoimmunity in a variety of disease models,
The specific profile of cytokines produced by CD4 T cells as well as in host defenses against a broad spectrum of extracellular
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allows further functional subdivision (Chapters 16, 18). 35,39 CD4 bacteria, fungi and other pathogens. Research continues to
T cells elaborating the “inflammatory” cytokines involved in identify additional examples of CD4 T cells, which may become
effector functions of cell-mediated immunity, such as IL-2 and recognized as distinct subsets, whose function is governed by
IFN-γ, are designated Th1 cells. Th2 CD4 T cells synthesize other predominantly expressed cytokines to achieve specialized
cytokines, such as IL-4 and IL-13, which control and regulate effector responses.
antibody responses and activate cells that are involved in host One final category of CD4 cells, Tregs, plays a crucial role
defense against parasites. Differentiation of Th1 versus Th2 subsets suppressing the functions of other lymphocytes. Tregs can dif-
is a process substantially controlled by positive feedback loops, ferentiate either in the thymus (tTregs) or in the periphery
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being promoted particularly by IL-12 in the case of Th1 cells (pTregs). A third category of Tregs are induced in vitro (iTregs)
and IL-4 in the case of Th2 cells. It is important to note that (Chapter 18). These are commonly characterized by surface
generalizations regarding cytokine activity are usually oversim- expression of CD4 and CD25 and by nuclear expression of the
+
plifications, reflecting a substantial overlap and multiplicity of transcription factor Foxp3. Peripheral activation of CD25 Tregs
functions (Chapter 9). For example, although IL-2 was initially is via the TCRs; the cells are IL-2 dependent and apparently
identified as a T-cell growth factor, it also significantly affects require cell-to-cell contact for suppressive function. They can
B-cell differentiation. The prototypic inflammatory cytokine, suppress functions of both CD4 and CD8 T cells, as well as B
IFN-γ, which promotes differentiation of effector function of cells, NK cells, and NKT cells. In contrast to activation, suppressor
cytotoxic lymphocytes (CTLs) and macrophages, is also involved effects are independent of the antigen specificity of the target