The importance of the back–signal from T cells into antigen–presenting cells in determining susceptibility to parasites

Abstract

It has long been known that certain MHC class II genes can dominantly suppress immune responses and so increase susceptibility to parasite infections, but the mechanism has been unclear. Recent work has revealed one way in which this form of suppression may operate, through gating by MHC class II molecules of the back-signal from activated T cells into macrophages. The two known suppressive genes of the mouse are expressed in macrophages more extensively than are other class II genes. This is asscociated with suppression of IL-4 production resulting, we infer, from overproduction in the macrophages of IL-12, the counter-cytokine to IL-4. The lack of IL-4 may itself be immunosuppressive, even for Th2 responses, and excess IL-12 can overinduce the antiproliferative cytokine IFN-gamma. Although this mechanism requires further substantiation, we believe that it o¡ers a reasonable answer to an old conundrum.

Differential expression of major histocompatibility complex class II genes on murine macrophages associated with T cell cytokine profile and protective/suppressive effects

“…These data suggest that a highly expressed MHC class II molecule might exert its effect by facilitating CD40-CD40L ligation and thus enhancing IL-12 induction (18). For this to occur, it is likely that the trimolecular complex of MHC molecule, antigenic peptide, and T cell receptor must form.…”

“…When comparing the MHC class II expression at peak level, there are about 100-fold more I-A effect. This bias is predicted by the hypothesis that a facilitated interaction between T cells and macrophages would increase IL-12 production (18). Thus a pathway can be traced from a defined single-base promoter polymorphism, via extended expression of the class II gene, through a gating function of this expression, to the release of a counter-IL-4 cytokine, and so to a protective͞suppressive function.…”

“…Meanwhile others have shown that ligation of class II molecules on macrophages elicits prompt release of IL-12, mainly via facilitated ligation of CD40 (14); the same effect can be obtained with monocytes (15) and dendritic cells (16,17), although there the IL-12 release may occur too late to account for the early suppression of IL-4 production. It therefore seemed likely that the level of expression of an MHC class II molecule might gate this back signal from a T cell to its APC so that heightened or more extensive expression would increase the IL-12 signal and thus exert a protective͞suppressive effect via Th1 bias (18). To test this hypothesis, the expression of class II molecules from the four haplotypes H-2 b , H-2 d , H-2 k , and H-2 q was measured on fresh splenic macrophages, on activated macrophages represented by bone marrowderived macrophages (BMDMs), on fresh splenic B cells, and on lipopolysaccharide (LPS)-activated splenic B cells.…”

The Distribution of Variation in Regulatory Gene Segments, as Present in MHC Class II Promoters

“…Further information about the functional significance of this promoter polymorphism is likely to be acquired through expression studies on naturally occurring variants (for review, see Guardiola et al 1996;Müller and Mitchison 1997). More critical testing is likely to come from site-specific mutagenesis and promoter/exon reshuffling in cell lines and eventually in mice.…”

“…That is, however, an important question, and a similiar study including additional human MHC class II loci as well as intraspecific comparisons with a variety of other species is needed. There are other aspects of variation in human MHC class II promoters, including allele frequencies and the consequences of haplotype selection, that are important but necessitate extensive review, beyond the scope of the present work.Further information about the functional significance of this promoter polymorphism is likely to be acquired through expression studies on naturally occurring variants (for review, see Guardiola et al 1996;Müller and Mitchison 1997). More critical testing is likely to come from site-specific mutagenesis and promoter/exon reshuffling in cell lines and eventually in mice.…”