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1180 Part IX: Lymphocytes and Plasma Cells Chapter 76: Functions of T Lymphocytes: T-cell Receptors for Antigen 1181

normally constitute 25 to 35 percent of the peripheral T-cell popula- response becomes increasingly polarized once it develops along a Th1
tion. They recognize antigens presented by MHC class I molecules and or Th2 pathway, particularly upon protracted stimulation by chronic
differentiate into cytotoxic CD8 T cells. Their main function is lysis of infection or prolonged exposure to environmental antigens. Other fac-
the target cell bearing the surface antigens for which a cytotoxic T cell tors that drive polarization are chemokines (explaining the differential
is specific. Within this subset, there are a range of phenotypes defined expression of chemokine receptors on Th1/Th2 cells), eicosanoids, oxy-
both by function and expression of markers with an immunoregula- gen free radicals, various inflammatory mediators, and direct cell-to-
tory function. Blood T cells that solely express the CD4 surface antigen cell interaction with APCs.
are designated helper T cells. They normally comprise approximately Functionally, Th1 cells predominantly drive cellular immunity to
65 percent of blood T cells. Generally, their function is the production fight viruses and other intracellular pathogens, eliminate cancerous
of lymphokines upon activation by foreign antigens presented by MHC cells, and stimulate delayed-type hypersensitivity (DTH) skin reac-
class II molecules, regulating and/or assisting in the active immune tions. This is mostly achieved by stimulating macrophage Fc receptor
response. Helper T cells can differentiate into several subtypes, each expression, phagocytosis, and antigen presentation, enhancing the
secreting different cytokines to facilitate a different type of immune capacity of macrophages to kill intracellular pathogens. Th2 cells drive
response. humoral immunity and upregulate antibody production to fight extra-
cellular organisms. They initiate the antibody response to antigen by
activating naïve antigen-specific B cells to produce IgM antibodies,
CD4+ T-CELL SUBSETS subsequently stimulate the production of switched immunoglobulin
Th1 and Th2 Cells isotypes, including IgA, IgE, and neutralize and/or weakly opsonize
Based on distinct cytokine patterns upon activation, mature CD4+ subtypes of IgG (Chap. 75), probably via IL-4 as a B-cell stimulatory/
T cells may be divided into subsets–the first of which identified were growth factor. In addition to stimulating the production of IgE antibod-
named T-helper type 1 (Th1) and T-helper type 2 (Th2). In general, Th1 ies, the cytokines made by Th2 cells induce differentiation of mast cells
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cells are a major source of interferon-γ (IFN-γ), and also the major T-cell and eosinophils. 34
population involved in activating macrophages and clearing intracellu- Several studies have indicated that Th2 polarization and accu-
lar pathogens. Th2 cells are a major source of IL-4 and are important mulation at inflammatory sites is likely to trigger the hypersensitiv-
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for the generation of immunoglobulin (Ig) E, the production of eosin- ity reaction in allergic diseases. On the other hand, these responses
ophils, and the immune defense against infections by parasites. Both are protective against metazoan parasite infections such as helminths:
subsets are produced from a noncommitted population of precursor Th2 responses are host protective while extracellular parasites migrate
T cells. The process by which commitment develops is called through the body, and reduce the number of parasites either through
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polarization. direct killing in the tissues or expulsion from the intestines. Other
In addition to IFN-γ, Th1 cells produce lymphotoxin β, IL-2, and studies demonstrate that eosinophilia and elevated IgE that accompany
IL-12, whereas Th2 cells also produce IL-5, IL-13, and IL-25. Human infection with Schistosoma mansoni are caused by the induction of
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Th1 and Th2 cells can also differ in the array of surface antigens or cytok- Th2-type cells in the immune response to parasite ova. The Th2 polar-
ine receptors they express. Th1 cells preferentially express CD26, mem- ization in these diseases/conditions is most likely a result of minimal
brane IFN-γ, the chemokine receptors CCR1 (CD191), CCR2 (CD192), IL-4 secretion during initial activation. If an antigen is present at high
CCR5 (CD195), CXCR3 (CD183), and CXCR6 (CD186), and the recep- concentrations but does not trigger acute inflammation and attendant
tor for IL-12 (IL-12R or CD212). Higher levels of the lymphocyte acti- production of IL-12, the local concentration of IL-4 increases over time
vation gene 3 (LAG-3 or CD223), a ligand for MHC class II antigens and induces a Th2 polarization of cells. On the other hand, pathogens
that is structurally related to CD4, have also been described. Th2 cells that induce acute inflammation and/or engage toll-like receptors on
preferentially express CD62L, the α chain of the IL-4 receptor (IL-4Rα), accessory cells and macrophages can promote production of IFN-γ and
the α chain of the IL-33 receptor (IL-33Rα), CD30, and the chemokine IL-12, thereby stimulating development of the immune response along
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receptors CCR3 (CD193), CCR4 (CD194), CCR8 (CDw198), and, to the Th1 pathway. Immune responses restricted to Th1 cells, for exam-
some extent, CXCR4 (CD184). 35–37 Distinctive expression levels of these ple, are observed in patients with leprosy who have developed cellular
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cytokine and chemokine receptors, along with distinctive binding activ- immunity to Mycobacterium leprae or M. tuberculosis, in patients
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ities for various endothelial selectins, most likely account for the differ- with Yersinia enterocolitica or arthritis triggered by infection with
ences in the response to cytokines and tissue-specific migration of these Borrelia burgdorferi. 47
helper T-cell subsets. However, it is probably overly simplistic to view the Th1 pathway
The cytokines produced by each subset also stimulate polariza- as being the more aggressive of the two, generating acute organ-
tion of additional T cells to the same subset, while inhibiting the polar- specific autoimmune diseases and inflammations, while the Th2 path-
ization of the other subset. In naïve CD4+ T cells, the Th1 cytokine way predisposes to atopic diseases and systemic autoimmune disease.
IFN-γ induces or activates the signal transducer and activator of tran- For example, Helicobacter pylori-associated peptic ulcer can be regarded
scription (STAT) 1, STAT4, and the T-box transcription factor T-BET, as a Th1-driven immunopathologic response to some H. pylori antigens,
while simultaneously modulating IL-2 and Th2 cytokines, resulting while deregulated and exhaustive H. pylori-induced T-cell–dependent
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in an attenuation of Th2 cell development (Fig. 76–3). Several other B-cell activation can support the onset of low-grade B-cell lymphoma.
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studies demonstrate that T-BET also physically interacts with other In addition, many chronic inflammatory and autoimmune conditions
transcription factors important for alternative T helper cell develop- such as rheumatoid arthritis (RA), type 1 diabetes, and multiple scle-
mental decisions to functionally repress the opposing subtype specific rosis (MS) are mixed Th1/Th2 conditions, and a clear Th1/Th2 bias has
gene expression programs and promote Th1 development. Similarly, also not been identified yet for many types of cancer. 34
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IL-4 activates or enhances the expression STAT5, STAT6, and GATA3,
transcription factors that play important roles in Th2 cell development CD4+CD25+ Regulatory T Cells
(Fig. 76–3). Another Th2 cytokine, IL-10, inhibits Th1 cell activation, Another type of CD4 cells that suppresses rather than provides helper
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thereby limiting the production of Th1-type cytokines. Because of these activity are regulatory T (T REG ) cells. T REGs possess potent suppressive
self-amplifying and mutually excluding feedback loops, an immune capacity and can exert diverse suppressive mechanisms allowing them

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