Major Histocompatibility Complex Regulation of Cytokine Production

Abstract

This review describes the phenomenon of the major histocompatibility complex (MHC) control of cytokine production both in experimental animals and in humans. H-2 (mouse MHC) regulates which type of cytokine is selectively produced in response to the hapten trinitrophenyl (TNP). T cells from TNP-immune H-2k mice produce interferon-gamma (IFN-gamma), interleukin-2 (IL-2), IL-3, IL-5, tumor necrosis factor-alpha (TNF-alpha), IL-10, and very low levels of IL-4 on reexposure to the specific antigen in vitro. By contrast, T cells from H-2d mice produce IL-3, TNF-alpha, IL-10, and IL-4 but very low levels of IL-2, IL-5 and IFN-gamma. As MHC-congenic matched strains (BALB/k and BALB/c) are used, this makes it unlikely that non-MHC genes influence the class of response observed. A similar pattern of haplotype regulation of cytokine production is observed in humans. In fact, peripheral blood mononuclear cells from HLA-B8,DR3-positive and negative individuals differ in their ability to produce IL-2, IL-5, and IFN-gamma on stimulation with the mitogen phytohemagglutinin while producing similar amounts of IL-4, IL-6, and IL-10. The following main considerations emerge from these observations. The MHC/peptide complex generated after antigen immunization, indicates which class of cytokine production is preferentially induced and, therefore, the outcome of the immune response. Furthermore, MHC genotype may affect cytokine production (and then immune responses) by completely different mechanism(s), that is, by an antigen-nonspecific control that does not depend on the ability of MHC molecules to bind in different ways the different peptides. Accurate control of the functional repertoire of an immune response is a critical parameter in response to infections as well as in immunopathology. MHC control of the class of the immune response at the level of cytokine production is a sophisticated way in which this occurs. This control might be involved in adaptive immune responses to infections as well as in immunopathology.

HLA‐A, B, Cw and DRB1, DRB3/4/5, DQB1, DPB1 Frequencies in German Immunoglobulin A‐Deficient Individuals

“…an increased risk of developing autoimmune diseases, impaired T-cell function, or imbalance in cytokine production [22]. The theory that the major histocompatibility complex (MHC) controls the pattern of cytokine production and in¯uences the levels of circulating immunoglobulins has been described previously [23]. HLA-B8:DR3 subjects from a normal population showed reduced levels of serum IgA.…”

“…Stimulated mononuclear cells from those individuals produced reduced amounts of interleukin (IL)-2, IL-5 and interferon (IFN)-g. Although there are controversial results regarding the importance of IL-5 for IgA synthesis in humans [1], impaired IL-5 production might be involved in the pathogenesis of IgA de®ciency. Most studies reveal an impairment of in vivo and in vitro immune responses in HLA-B8:DR3 subjects that might contribute to the development of IgA de®ciency [23].…”

Cytokine gene polymorphism in human disease: on-line databases

“…315 In this regard, DR3 has received the greatest attention. T cell activation varies in DR3-positive individuals, perhaps because of diminished CD69 expression, 316 as do cytokines themselves 317 particularly in regard to autoimmune DR3 positive subjects. 318 Apoptosis may differ because these individuals have diminished expression of CD95 (FAS 319 ) and indeed lower total lymphocyte counts have been described in aassociation with B8-DR3.…”

T cells and aging (update February 1999)

“…In the absence of type 2 cytokines, priming for IFN-gamma production occurs, but this is markedly enhanced by IL 12 (260). Although other factors may play a role in the determination of cytokine-producing phenotype, such as antigen dose, MHC type of antigenpresenting cell (261), and expression of accessory molecules and hormones, these effects appear to be secondary to the dominant role of cytokines.…”