nature medicine:Protective HIV-specific CD8+ T cells evade Treg cell suppression

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Specific variants of the human leukocyte antigens HLA-B27 and HLA-B57 are associated with control of HIV-1 infection, but the mechanisms responsible for this protection are not clear. Here, Elahi et al. show that CD8+ cytotoxic T cells restricted by these HLA variants are less susceptible to suppression by and are able to kill regulatory T cells, which may account for their sustained proliferative capacity during chronic HIV-1 infection.


Protective HIV-specific CD8+ T cells evade Treg cell suppression

Specific human leukocyte antigens (HLAs), notably HLA-B*27 and HLA-B*57 allele groups, have long been associated with control of HIV-1. Although the majority of HIV-specific CD8+ T cells lose proliferative capacity during chronic infection, T cells restricted by HLA-B*27 or HLA-B*57 allele groups do not. Here we show that CD8+ T cells restricted by 'protective' HLA allele groups are not suppressed by Treg cells, whereas, within the same individual, T cells restricted by 'nonprotective' alleles are highly suppressed ex vivo. This differential sensitivity of HIV-specific CD8+ T cells to Treg cell–mediated suppression correlates with their expression of the inhibitory receptor T cell immunoglobulin domain and mucin domain 3 (Tim-3) after stimulation with their cognate epitopes. Furthermore, we show that HLA-B*27– and HLA-B*57–restricted effectors also evade Treg cell–mediated suppression by directly killing Treg cells they encounter in a granzyme B (GzmB)-dependent manner. This study uncovers a previously unknown explanation for why HLA-B*27 and HLA-B*57 allele groups are associated with delayed HIV-1 disease progression.