Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis

Abstract

Rationale: The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis.Objectives: To identify T-cell-dependent mechanisms that are protective in tuberculosis.Methods: Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood.Measurements and Main Results: At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-g-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%). Conclusions: Our data define an unconventional CD81 T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.

Tuberculosis patients display a high proportion of CD8+ T cells with a high cytotoxic potential

“…CD8 + T cells called “polycytotoxic T cells” were recently defined and are present in bronchoalveolar lavage cells in TB patients. They are lipoarabinomannan (LAM)‐responsive T cells that contribute to disease outcome . By contrast, it has been demonstrated that TB patients have LAM in their peripheral blood .…”

“…They are lipoarabinomannan (LAM)responsive T cells that contribute to disease outcome. 31 By contrast, it has been demonstrated that TB patients have LAM in their peripheral blood. 32 We suggest that the high cytotoxic ability shown by CD8 + T cells in TB patients could be a consequence of the frequent interaction of LAM-CD8 + T cells in peripheral blood.…”

T Cell Responses to Mycobacterial Glycolipids: On the Spectrum of “Innateness”

“…Most of the data regarding mycolipid-specific T cells have been obtained through studies of in vitro-derived T cell clones, which have been shown to express IFN-γ, TNF, and IL-17, as well as lyse M.tb-infected cells and control M.tb replication in vitro (13,16,18,38,55,82). T cells with different affinities for GMM-loaded CD1b tetramers have been shown to have different functional capabilities.…”

CD1b-restricted GEM T cell responses are modulated byMycobacterium tuberculosismycolic acid meromycolate chains

“…In humanized mice, CD1b-restricted T cells generate polyfunctional responses which reduce mycobacterial proliferation in vitro and accumulate in mycobacteria-induced lung granulomas in vivo (19). Furthermore, CD1b-restricted polycytotoxic T cells in bronchioalveolar fluid were recently shown to limit Mtb growth ex vivo (20). In TB patients, CD1b-restricted T cell numbers in peripheral blood and at the site of infection expand and contract markedly according to pathogen burden, and therefore may contribute to the immune response to Mtb (18).…”