CD4+ T cell receptor repertoire and antigen-specific T cell responses in people who “resist” infection of Mycobacterium tuberculosis 3108

Abstract Description Mycobacterium tuberculosis (Mtb) is the cause of tuberculosis that is usually transmitted through contact with TB patients. Several studies described “resisters” who exposed to Mtb for years but consistently negative for Mtb diagnosis, which assessed via IFNγ response to Mtb antigens ESAT6 and CFP10 (QFT test) and skin test. CD4 T cells are critical in combating Mtb. Delineating the T cell receptor (TCR) repertoire, antigen specificities, and phenotypes of CD4 T cells in “resisters” can uncover features of protective T cells against Mtb and guide vaccine development. However, analyzing T cells against Mtb is hindered by the vast diversity of human TCR repertoire, HLAs, and Mtb genome, and determining TCR antigen specificities has been challenging due to a lack of appropriate methods. To overcome the challenges, we used BD Rhapsody to acquire millions of TCRs of a well-described Uganda TB household cohort. Leveraging GLIPH3, an advanced TCR analysis algorithm, we identified TCR clusters uniquely enriched in “resisters”. To determine the antigen specificities of these TCRs, we developed an epitope screening system with a novel reporter T cell, which can display TCR candidates and report the recognition of TCR and peptide-MHC. With this system, we identified two epitopes in Rv2140c and ESAT6. By visiting QFT- PBMCs of Cape Town ACS cohort, we delineated unique Tfh phenotype in Rv2140c+ T cells with TGFβ expression. In contrast, the ESAT6+ T cells exhibited typical Th1 phenotype. Topic Categories Microbial, Parasitic, and Fungal Immunology (MPF)