Linking genetics and resistance to infection

All immunologists know the old adage that MHC polymorphisms are believed to benefit individuals by allowing the presentation of a broad array of antigenic peptides to T cells. But, direct evidence to support this proposed link between MHC haplotype and resistance to infection has been lacking so far. Now, Janko Nikolich-Žugich's lab provides evidence that, in contrast to this widely held view, MHC polymorphisms can influence immune defence by allowing the best T-cell precursors to be selected from a diverse T-cell receptor (TCR) repertoire.

To investigate how MHC polymorphisms influence MHC class-I-restricted T-cell responses, the authors used the mouse strains C57BL/6 (B6; MHC haplotype H-^2b) and B6.C-H-2bm8 (bm8; MHC haplotype H-^2bm8), the MHC molecules of which differ by only four amino acids located in the floor of the peptide-binding groove. MHC class I molecules from both strains bind HSV-8p, an immunodominant peptide from glycoprotein B of Herpesvirus hominis type 1 (HVH1).

When challenged with HVH1, bm8 mice were 3–4 times more resistant to infection than were B6 mice. When CD8⁺ T cells were depleted from the mice, no differences between the strains were observed in terms of resistance to infection, which indicates that MHC class-I-dependent immune responses govern resistance to infection. In (B6 × bm8) F₂ hybrid mice, a single copy of H-2K^bm8 conferred enhanced resistance.

In both B6 and bm8 mice, ∼90% of cytotoxic T lymphocyte (CTL) responses to HVH1 are specific for the immunodominant peptide HSV-8p. Transfer of HSV-8p-specific T cells from bm8, but not B6, mice into F₁ hybrids conferred significant protection against infection, which indicates that differences in a single allele can enhance protection in a T-cell-dependent manner.

How does this monoallelic difference lead to enhanced protection? Differential peptide binding to MHC molecules was not the answer, because the kinetics of binding of HSV-8p to H-2K^b and to H-2K^bm8 were identical. The possibilitity that H-2K^b-mediated negative selection interferes with resistance was ruled out also.

Because H-2K^bm8 positively selects CD8⁺ T cells with a broader TCR repertoire than does H-2K^b, the authors next decided to investigate the influence of the TCR repertoire on the quantity and quality of HSV-8p-specific CTL responses. No quantitative differences in the numbers of CTL precursors that were mobilized in response to infection were observed between the strains. In B6 mice, the CTL repertoire is dominated by TCRs with two variable-region (V) β-chains, Vβ8 and Vβ10, whereas bm8 mice use these Vβ chains plus five others. The number of Vβ8+ T cells is similar in each strain. If the magnitude of the CTL response is an important parameter, depletion of Vβ8⁺ T cells — which comprise ∼15–25% of the total response to HSV-8p in both strains — should have a similar relative effect in each strain. But, if breadth of the repertoire is important, depletion of Vβ8⁺ T cells would affect the outcome differentially. When Vβ8⁺ T cells were depleted, B6 mice showed enhanced mortality, whereas bm8 mice showed no difference in mortality compared with non-depleted mice. This provides evidence that CTL repertoire diversity can influence resistance to infection. In addition, CTLs from bm8 mice had higher avidity for antigen and were better able to kill target cells in a CTL assay.

The authors suggest that MHC-polymorphism-driven diversification of the TCR repertoire in bm8 mice allows high-avidity CTLs to be generated more readily, and that this might be the link between MHC polymorphism and resistance to infection.