Immunology and Microbiology Program, Graduate School of Biomedical Sciences; Department of Microbiology and Physiological Systems
Bacteria | Bacterial Infections and Mycoses | Bacteriology | Immunity | Immunology of Infectious Disease | Immunopathology | Pathogenic Microbiology
CD8 T cells provide limited protection against Mycobacterium 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 the esxH gene. In C57BL/6 mice, 30-50% of pulmonary CD8 T cells recognize the TB10.44-11 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 in esxH, which frequently occur in lineage 1 strains, to test this "decoy hypothesis". Using the clinical isolate 667, which contains an EsxHA10T polymorphism, we observe a drastic change in the hierarchy of CD8 T cells. Using isogenic Erd.EsxHA10T and Erd.EsxHWT 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-Kb 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 TB10.44-11epitope. 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.
T cells, Cytotoxic T cells, Macrophages, Mycobacterium tuberculosis, Immune response, Antigen processing and recognition, T helper cells, Spleen
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Copyright: © 2020 Sutiwisesak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
Sutiwisesak R, Hicks ND, Boyce S, Murphy KC, Papavinasasundaram K, Carpenter SM, Boucau J, Joshi N, Le Gall S, Fortune SM, Sassetti CM, Behar SM. A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response. PLoS Pathog. 2020 Oct 19;16(10):e1009000. doi: 10.1371/journal.ppat.1009000. PMID: 33075106; PMCID: PMC7597557. Link to article on publisher's site
Sutiwisesak R, Hicks ND, Boyce S, Murphy KC, Papavinasasundaram K, Carpenter SM, Boucau J, Joshi N, Le Gall S, Fortune SM, Sassetti CM, Behar SM. (2020). A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response. Open Access Publications by UMMS Authors. https://doi.org/10.1371/journal.ppat.1009000. Retrieved from https://escholarship.umassmed.edu/oapubs/4435
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