A natural polymorphism of EsxH in Mycobacterium tuberculosis disrupts the immunodominant CD8 T cell response.

Abstract

Abstract Mycobacterium tuberculosis (Mtb), the cause of tuberculosis (TB), is an intracellular bacterium that evades antibacterial immunity. As control of Mtb requires T cell immunity, most vaccine strategies focus on eliciting protective T cells. How Mtb benefits from promoting T cell activation or evading T cell recognition is not certain. Here, we took advantage of a naturally occurring Mtb polymorphism to address this question in mouse model. EsxH elicits an immunodominant CD8 T cell response. At the peak of immunity against Mtb in C57BL/6 mice, 30–50% of CD8 T cells are specific for EsxH4–11. Clinical Isolate 667 (CI667) is an Mtb strain containing a polymorphism in EsxH that has a single amino acid change of WT EsxH4–11 epitope from IMYNYPAM into IMYNYPTM (A10T). We hypothesized that this naturally occurring polymorphism would alter the hierarchy of CD8 T cell responses elicited by Mtb. Following Erdman (WT) Mtb infection of C57BL/6 mice, CD8 T cells respond to three distinct epitopes, including the reported immunodominant EsxH4–11 epitope. In contrast, there was no response to any of EsxH epitopes after CI667 infection. Instead, the subdominant response to the 32C antigen became dominant. In BALB/c mice, CI667 stimulated a reduced but detectable CD8 response to EsxH20–28; the CD4 response to EsxH74–88 was similar to WT Mtb infection. These results show that naturally occurring polymorphisms can have drastic effects on T cell immunity. We hypothesize that EsxH acts as a decoy antigen, and distracts the CD8 response from focusing on antigens that are presented by infected macrophages and protective. We are in the process of testing this hypothesis by developing isogenic Mtb strains that express EsxHErdman or EsxHCI667.