The immune system serves essential functions in protection from numerous pathogenic organisms and, in general, is not harmful to the host. The process by which the immune response is restrained or controlled is termed immunoregulation. A number of different aspects of the immune system contribute to this process of immunoregulation, some of the most important being signals from antigenā€presenting cells by ostimulatory molecules, the effects of cytokines and apoptotic cell death.

Keywords: immunology; lymphocytes; cytokines; tolerance; apoptosis

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; TH, T helper cell.

Figure 2.

Immunoregulation and the TH1–TH2 paradigm. Undifferentiated helper T cells (TH0) only produce interleukin (IL)‐2. IL‐12, produced by macrophages in response to pathogens, drives TH1 differentiation. In conjunction with IL‐18, IL‐12 causes interferon (IFN) γ production, which further activates monocytes. When differentiated, TH1 cells produce IL‐2, IFNγ and lymphotoxin (LT). Among their actions, these cytokines serve to activate macrophages further. In contrast, TH2 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.


Further Reading

Abbas AK, Lichtman AH and Pober JS (1997) Cellular and Molecular Immunology, 3rd edn. Philadelphia: W.B. Saunders.

Kuo CT and Leiden JM (1999) Transcriptional regulation of T lymphocyte development and function. Annual Review of Immunology 17: 149–188.

Leonard WJ and O’Shea JJ (1998) Jaks and STATs: biological implications. Annual Review of Immunology 16: 293–322

Matzinger P (1994) Tolerance, danger and the extended family. Annual Review of Immunology 12: 991–1045.

McDermott MF, Aksentijevich I, Galon J et al. (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97: 1–20.

O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8: 275–283.

O’Shea JJ (1997) Jaks, STATs, cytokine signal transduction, and immunoregulation: are we there yet? Immunity 7: 1–11.

Parijs LV and Abbas A (1998) Homeostasis and self‐tolerance in the immune system: turning lymphocytes off. Science 280: 243–248.

Paul WE (1999) Fundamental Immunology. New York: Raven Press.

Rosen FS, Cooper MD and Wedgwood RJ (1995) The primary immunodeficiencies. New England Journal of Medicine 333: 431–440.

Schwartz RH (1996) Models of T cell anergy: is there a common molecular mechanism? Journal of Experimental Medicine 184: 1–8.

Szabo SJ, Glimcher LH and Hoi IC (1997) Genes that regulate interleukin‐4 expression in T cells. Current Opinion in Immunology 9: 776–781.

Wang J and Lenardo MJ (1997) Molecules involved in cell death and peripheral tolerance. Current Opinion in Immunology 9: 818–825.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
O’Shea, John J, and Nutman, Thomas B(Apr 2001) Immunoregulation. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0000952]