MR1-restricted T cell clonotypes are associated with 'resistance' to M.tuberculosis infection

• Published in: bioRxiv
• Main Authors: Cross, Deborah L, Layton, Erik D, Yu, Krystle Kq, Smith, Malisa T, Aguilar, Melissa S, Li, Shamin, Mayanja-Kizza, Harriet, Stein, Catherine M, Boom, William Henry, Hawn, Thomas R, Bradley, Philip, Newell, Evan, Seshadri, Chetan
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 13.10.2022
• Subjects: Antigens; Flow cytometry; Infections; Lymphocytes; Lymphocytes T; Natural killer cells; Peripheral blood; T cell receptors; Tuberculosis; γ-Interferon
• DOI: 10.1101/2022.10.12.511825

T cells are required for a protective immune response against the human adapted pathogen Mycobacterium tuberculosis (M.tb). We recently described a cohort of Ugandan household contacts of tuberculosis cases that appear to "resist" M.tb infection (RSTRs) and showed that these individuals harbor IFN-γ independent T cell responses to M.tb-specific peptide antigens. However, T cells also recognize non-protein antigens via antigen presenting systems that are independent of genetic background, leading to their designation as donor-unrestricted T (DURT) cells. We used combinatorial tetramer staining and multi-parameter flow cytometry to comprehensively characterize the association between DURTs and "resistance" to M.tb infection. We did not observe a difference in peripheral blood frequencies of invariant natural killer T (iNKT) cells, germline encoded mycolyl-reactive (GEM) T cells, or γδ T cells between RSTRs and matched controls with latent M.tb infection (LTBIs). However, we did observe a 1.65-fold increase in frequency of circulating MR1-restricted T (MR1T) cells among RSTRs in comparison with LTBI (p=0.03). Multi-modal single cell RNA-sequencing of 18,251 MR1T cells sorted from a subset of donors revealed 5150 unique clonotypes that expressed a common transcriptional program, the majority of which were private. Deep sequencing of the TCR-α repertoire revealed several DURT clonotypes that were expanded among RSTRs, including at least two MR1T clonotypes. Taken together, our data reveal unexpected donor-specific diversity in the TCR repertoire of human MR1T cells as well as associations between MR1 clonotypes and "resistance" to M.tb infection. Competing Interest Statement The authors have declared no competing interest.