Functions of H2 class II molecules

Study of the class II molecules of the mouse MHC has provided a great deal of the current information on the functional roles played by class II molecules in the immune system. Genetic manipulations which are feasible in defined inbred mouse strains have allowed investigators to examine in great detail how class II molecules regulate responses to antigen. The advent of transgenic and knockout mouse technology in more recent years has created additional opportunities for studying the roles of class II molecules, in both immune system development and function. Following the development of inbred, genetically defined strains of rodents, it was observed that the allelic forms of class II molecules expressed by an animal determine its responsiveness to certain soluble antigens. In fact, it was this property of mouse class II genes which was the basis for their early designation as immune response (lr) genes. However, it was not until decades later that details of how class II molecules exert this regulatory effect were understood.

A major advance in this understanding occurred in the early 1980s, with two major discoveries, each involving the contributions of many investigators. The isolation and characterization of the T cell antigen receptor (TCR) in 1983-1984 demonstrated that the same receptor recognizes both antigen and MHC molecules on an antigen-presenting cell (APC). This implied that antigen must physically associate with MHC molecules to be recognized by a T cell. The subsequent discovery (1985-1987) that purified MHC molecules bind tightly to antigenic peptides in an allele-specific manner revealed the nature of the critical role of MHC molecules in antigen presen tation. In subsequent years, the peptide-binding sites of both class I and class II MHC] molecules have been crystallized, and physical characteristics of these binding sites determined.

The ability to bind antigenic peptides and present them to T cells endows class II molecules with their major functional role - to effect the selection and stimulation of T cells by delivering signals through the T cell antigen receptor complex. The study of transgenic and knockout mice has revealed that when and where class II molecules are expressed during development of the immune system profoundly affects the development of T cell populations and the T cell antigen receptor repertoire. Class II thus plays a pivotal role in the ability of T cells to distinguish self from nonself and to react appropriately to antigen stimulation. It is not surprising, therefore, that the expression and peptide-binding properties of particular allelic forms of class II molecules are also implicated in the development of some autoimmune diseases. In the mouse, H2 class II molecules have been shown to play important roles in the development of experimental models of insulin-dependent diabetes, autoimmune encephalitis, collagen-induced arthritis and a murine form of lupus nephritis, among others. Conversely, a lack of class II expression from the earliest stages of development results in profound defects in the development ot CD4+ helper T cells and in both cellular and hum oral responses.

Class II molecules have also been shown to deliver signals to cells which constitutivelv express them, such as B cells and monocytes. Ligation of class II molecules on mouse B cells in vitro, alone or in combination with ligation of the B cell antigen receptor, can induce or enhance cell proliferation, antibody secretion, homotypic adhesion and IL-6 production. The molecular events involved in this signaling pathway are not well defined, but evidence has been presented for the involvement of both tyrosine and serine/threonine kinases, and the elevation of intracellular cAMP. Class II signals have also been shown to enhance signals delivered via the B cell receptor, CD40. It is not yet clear what role such signals mighr play in the regulation of in vivo immune responses, but recent in vivo studies in tumor immunity and using class II knockout mice have suggested that class II signals may affect the efficiency of antigen presentation by APCs.

See also: Alloantigens; Antigen-presenting cells; Antigen presentation via MHC class II molecules; MHC peptide-binding specificity; H2 class I; Immune response (lr) genes; MHC disease associations;

MHC, functions of; MHC restriction; Mixed lymphocyte reaction (MLR).

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