MAJOR HISTOCOMPATIBILITY COMPLEX REGULATION OF CYTOKINE PRODUCTION

This review describes the phenomenon of the major histocompatibility c omplex (MHC) control of cytokine production both in experimental anima ls 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-inmune H-2(k) 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 specif ic antigen in vitro. By contrast, T cells from H-2(d) mice produce IL- 3, TNF-alpha, IL-10, and IL-4 but very low levels of IL-2, IL-5 and IF N-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 resp onse observed. A similar pattern of haplotype regulation of cytokine p roduction is observed in humans. In fact, peripheral blood mononuclear cells from HLA-BS, DR3-positive and negative individuals differ in th eir ability to produce IL-2, IL-5, and IFN-gamma on stimulation with t he 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 immuniza tion, indicates which class of cytokine production is preferentially i nduced and, therefore, the outcome of the immune response. Furthermore , MHC genotype may affect cytokine production (and then immune respons es) by completely different mechanism(s), that is, by an antigen-nonsp ecific control that does not depend on the ability of MHC molecules to bind in different ways the different peptides. Accurate control of th e functional repertoire of an immune response is a critical parameter in response to infections as well as in immunopathology. MHC control o f the class of the immune response at the level of cytokine production is a sophisticated way in which this occurs. This control might be in volved in adaptive immune responses to infections as well as in inmuno pathology.