A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response

Author summary An important question for vaccine developers is the relative potency of CD4 vs. CD8 T cells against Mtb, as strategies differ for eliciting these different T cell subsets. Despite robust antigen-specific pulmonary CD8 T cell responses, CD4 T cells mediate more protection than CD8 T cells in the murine model. Most CD8 T cells recognize a single antigen, TB10.4, which is encoded by theesxHgene. Based on finding that TB10.4(4-11)-specific CD8 T cells poorly recognize Mtb-infected macrophages, we hypothesized that Mtb evades detection by CD8 T cells and focuses the CD8 T cell response on non-protective antigen. We termed these antigens decoy antigens. To test this hypothesis, we took advantage of a natural variant of theesxHgene, which contains an A10T polymorphism within the TB10.4(4-11)epitope. This polymorphism drastically alters the hierarchy of CD8 T cell responses elicited by Mtb. These data suggest that immunodomination by the TB10.4 epitope acts to suppress subdominant CD8 T cell responses to other Mtb antigens, impairing the CD8 T cell response to other Mtb antigens, some of which might be presented by Mtb-infected macrophages and be targets of protective immunity. Importantly, this single amino acid polymorphism, which does not significantly alter MHC-binding or T cell recognition, alters the half-life of the epitope and consequently, has a profound effect on CD8 T cell priming and recognition of infected cells. These data also provide a mechanism that could be exploited to manipulate the hierarchy of immunodominant responses. CD8 T cells provide limited protection againstMycobacterium tuberculosis(Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by theesxHgene. In C57BL/6 mice, 30-50% of pulmonary CD8 T cells recognize the TB10.4(4-11)epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected cells, thereby focusing CD8 T cells on nonprotective antigens. Here, we leverage naturally occurring polymorphisms inesxH, which frequently occur in lineage 1 strains, to test this decoy hypothesis. Using the clinical isolate 667, which contains an EsxH(A10T)polymorphism, we observe a drastic change in the hierarchy of CD8 T cells. Using isogenic Erd.EsxH(A10T)and Erd.EsxH(WT)strains, we prove that this polymorphism alters the hierarchy of immunodominant CD8 T cell responses. Our data are best explained by immunodomination, a mechanism by which competition for APC leads to dominant responses suppressing subdominant responses. These results were surprising as the variant epitope can bind to H2-K(b)and is recognized by TB10.4-specific CD8 T cells. The dramatic change in TB10.4-specific CD8 responses resulted from increased proteolytic degradation of A10T variant, which destroyed the TB10.4(4-11)epitope. Importantly, this polymorphism affected T cell priming and recognition of infected cells. These data support a model in which nonprotective CD8 T cells become immunodominant and suppress subdominant responses. Thus, polymorphisms between clinical Mtb strains, and BCG or H37Rv sequence-based vaccines could lead to a mismatch between T cells that are primed by vaccines and the epitopes presented by infected cells. Reprograming host immune responses should be considered in the future design of vaccines.