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Unconventional T cells that recognize mycobacterial antigens are of great interest as potential vaccine targets against tuberculosis (TB). This includes donor-unrestricted T cells (DURTs), such as mucosa-associated invariant T cells (MAITs), CD1-restricted T cells, and [gamma][delta] T cells. We exploited the distinctive nature of DURTs and [gamma][delta] T cell receptors (TCRs) to investigate the involvement of these T cells during TB in the human lung by global TCR sequencing. Making use of surgical lung resections, we investigated the distribution, frequency, and characteristics of TCR[delta] in lung tissue and matched blood from individuals infected with TB. Despite depletion of MAITs and certain CD1-restricted T cells from the blood, we found that the DURT repertoire was well preserved in the lungs, irrespective of disease status or HIV coinfection. The TCR[delta] repertoire, in contrast, was highly skewed in the lungs, where it was dominated by V[delta]1 and distinguished by highly localized clonal expansions, consistent with the nonrecirculating lung-resident [gamma][delta] T cell population. These data show that repertoire sequencing is a powerful tool for tracking T cell subsets during disease., Introduction Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains the leading cause of death from an infectious agent (Global Tuberculosis Report, WHO, 2018 (1). Although treatable with antibiotics, there is [...]

T cell immunity is essential for the control of tuberculosis (TB), an important disease of the lung, and is generally studied in humans using peripheral blood cells. Mounting evidence, however, indicates that tissue-resident memory T cells (Trms) are superior at controlling many pathogens, including Mycobacterium tuberculosis (M. tuberculosis), and can be quite different from those in circulation. Using freshly resected lung tissue, from individuals with active or previous TB, we identified distinct [CD4.sup.+] and [CD8.sup.+] Trm-like clusters within TB-diseased lung tissue that were functional and enriched for IL- 17-producing cells. M. tuberculosis-specific [CD4.sup.+] T cells producing TNF-[alpha], IL-2, and IL-17 were highly expanded in the lung compared with matched blood samples, in which [IL-17.sup.+] cells were largely absent. Strikingly, the frequency of M. tuberculosis-specific lung T cells making IL-17, but not other cytokines, inversely correlated with the plasma IL-1[beta] levels, suggesting a potential link with disease severity. Using a human granuloma model, we showed the addition of either exogenous IL-17 or IL-2 enhanced immune control of M. tuberculosis and was associated with increased NO production. Taken together, these data support an important role for M. tuberculosis-specific Trm-like, IL-17-producing cells in the immune control of M. tuberculosis in the human lung., Introduction Tuberculosis (TB), caused by the bacterium Mycobacterium tuberculosis (M. tuberculosis), remains a leading cause of death from infectious disease worldwide (1). Despite the availability of anti-TB treatment, difficulties in [...]