Figure 1. Mechanisms that regulate immune responses. (a) Foreign antigens are presented to T cells by antigen-presenting cells (APCs) such as macrophages, B cells and dendritic cells. T cells recognize foreign antigen by virtue of their clonotypic T-cell antigen receptors (TCRs). Occupancy of the TCR initiates a series of biochemical events that lead to activation of T cells; however, the T cells are not fully activated unless they also receive signals from costimulatory molecules like CD28, which binds to B7 molecules on APCs. When fully activated, T cells produce cytokines, some of which enhance inflammatory and immune responses whereas others inhibit. Still others regulate the type of immune response, promoting allergic or cell-mediated responses. (b) If T cells do not receive signals from CD28, and if they are unable to produce and respond to cytokines, they may become anergic or nonresponsive. (c) In addition, after activation T cells upregulate another molecule, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) which also binds B7 molecules, in contrast to CD28, CTLA4 transmits signals that inhibit lymphocyte activation. (d) When activated, T cells also express the molecules Fas and Fas ligand (FasL). Interaction of these molecules causes lymphocytes to undergo apoptotic cell death, thus constraining immune responses. Lymphocytes can also die because of the lack of cytokines; this is termed cytokine withdrawal apoptosis. IFN, interferon; IL, interleukin; MHC, major histocompatibility complex; TGF, transforming growth factor; T_H, T helper cell.

Figure 2. Immunoregulation and the T_H1–T_H2 paradigm. Undifferentiated helper T cells (T_H0) only produce interleukin (IL)-2. IL-12, produced by macrophages in response to pathogens, drives T_H1 differentiation. In conjunction with IL-18, IL-12 causes interferon (IFN) production, which further activates monocytes. When differentiated, T_H1 cells produce IL-2, IFN and lymphotoxin (LT). Among their actions, these cytokines serve to activate macrophages further. In contrast, T_H2 cells produce IL-4, IL-5 and IL-10. IL-4 inhibits macrophage activation, causes class switching so that B cells produce immunoglobulin E, and is a growth factor for mast cells. IL-5 activates eosinophils and IL-10 inhibits immune responses.

Figure 3. Signal transduction by type I and type II cytokines. Cytokines bind to the extracellular domain of transmembrane cytokine receptors, causing them to cluster. Janus kinases (JAKs) are protein tyrosine kinases that bind to the intracellular domain of cytokine receptors; the aggregation of receptors causes the JAKs to become activated. The activated JAKs phosphorylate substrates including the cytokine receptor. The phosphorylated receptor then is recognized by proteins that have specialized SH2 domains, which recognize phosphotyrosine. The signal transducer and activator of transcription (STAT) family of transcription factors have SH2 domains; they bind cytokine receptors and are themselves phosphorylated. The SH2 domains of the STATs allow them to dimerize, translocate to the nucleus, bind deoxyribonucleic acid (DNA) and regulate gene transcription.