A significant portion of the world’s population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) Over half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A*24, HLA-B*27, HLA-B*53 and HLA-B*58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B*44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy.

We have generated a panel of transgenic mice expressing HLA-A*01:03, -A*24:02, -B*08:01, -B*27:05, -B*35:01, -B*44:02, or -C*07:01 as chimeric monochain molecules (i.e., appropriate HLA α1α2 H chain domains fused with a mouse α3 domain and covalently linked to human β2-microglobulin). Whereas surface expression of several transgenes was markedly reduced in recipient mice that coexpressed endogenous H-2 class I molecules, substantial surface expression of all human transgenes was observed in mice lacking H-2 class I molecules. In these HLA monochain transgenic/H-2 class I null mice, we observed a quantitative and qualitative restoration of the peripheral CD8+ T cell repertoire, which exhibited a TCR diversity comparable with C57BL/6 WT mice. Potent epitope-specific, HLA-restricted, IFN-γ–producing CD8+ T cell responses were generated against known reference T cell epitopes after either peptide or DNA immunization. HLA-wise, these new transgenic strains encompass a large proportion of individuals from all major human races and ethnicities. In combination with the previously created HLA-A*02:01 and -B*07:02 transgenic mice, the novel HLA transgenic mice described in this report should be a versatile preclinical animal model that will speed up the identification and optimization of HLA-restricted CD8+ T cell epitopes of potential interest in various autoimmune human diseases and in preclinical evaluation of T cell–based vaccines.

HFE, an MHC class Ib molecule that controls iron metabolism, can be directly targeted by cytotoxic TCR αβ T lymphocytes. Transgenic DBA/2 mice expressing, in a Rag 2 KO context, an αβ TCR that directly recognizes mouse HFE (mHFE) were created to further explore the interface of HFE with the immune system. TCR-transgenic mHfe WT mice deleted mHFE-reactive T cells in the thymus, but a fraction of reprogrammed cells were able to escape deletion. In contrast, TCR-transgenic mice deprived of mHFE molecules (mHfe KO mice) or expressing a C282→Y mutated mHFE molecule -the most frequent mutation associated with human hereditary hemochromatosis -positively selected mHFEreactive CD8 + T lymphocytes and were not tolerant toward mHFE. By engrafting these mice with DBA/2 WT (mHFE + ) skin, it was established, as suspected on the basis of similar engraftments performed on DBA/2 mHfe KO mice, that mHFE behaves as an autonomous skin-associated histocompatibility antigen, even for mHFE-C282→Y mutated mice. By contrast, infusion of DBA/2 mHFE + mice with naïve mHFE-reactive transgenic CD8 + T lymphocytes did not induce GVHD. Thus, tolerance toward HFE in mHfe WT mice can be acquired at either thymic or peripheral levels but is disrupted in mice reproducing human familial hemochromatosis. These data raise the possibility that mHFE could be a histocompatibility antigen autonomously, not only for mHfe KO mice but also for mice with the HFE C282Y mutation.To answer this question and to ascertain the mechanisms through which tolerance toward mHFE is acquired, DBA/2 mice that expressed a transgenic TCR that directly recognizes mHFE were created in either a mHfe WT, mHfe KO or mHfe-C282→Y knock-in/mHfe KO heterozygous (mHfe-C282→Y mutated) context.Whereas the TCR-transgenic CD8 + T lymphocytes are positively selected in both mHfe KO and mHfe-C282→Y mutated mice, in mHfe WT mice, tolerance toward HFE is mainly acquired in the thymus by clonal deletion with, however, a fraction of cells escaping deletion by downregulating their TCR. This report further demonstrates that mHFE is autonomously a skin-associated histocompatibility antigen, not only for DBA/2 mHfe KO mice, but also for mice carrying the C282→Y HFE mutation responsible for human hereditary hemochromatosis. By contrast, HFE appears, at least alone, to be deprived of GVHD-induction potential. Results TCR-transgenic mHFE KO and WT mice T-cell analysisThe αβ TCR of a CTL clone that was previously shown to recognize mHFE directly [4] was used for the transgenesis of C57BL/6 × DBA/2 F1 mice. Founders were crossed with either mHfe/Rag 2 double or mHfe WT/Rag 2 single KO DBA/2 mice. Rag 2 KO/ H-2 d+/+ /α +/− β +/− TCR-transgenic animals were selected that were either mHfe WT or mHfe KO. Their thymocytes and splenocytes were stained, in parallel with cells from DBA/2 WT and DBA/2 Rag 2 KO mice, with anti-CD4 and anti-CD8 mAb (thymocytes) and anti-TCRβ and either anti-CD8 or anti-CD4 mAb (splenocytes). The gating strategy is shown in Supporting Information Figure 1. In the absence of mHF...

No abstract