Mpande, Cheleka A. M. Dintwe, One B. Musvosvi, Munyaradzi Mabwe, Simbarashe Bilek, Nicole Hatherill, Mark Nemes, Elisa J. Scriba, Thomas Team, The SATVI Clinical Immunology Table_2.PDF Background<p>Maintenance of long-lasting immunity is thought to depend on stem cell memory T cells (T<sub>SCM</sub>), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (T<sub>CM</sub>) or effector (T<sub>EFF</sub>) T cells. Our knowledge of T<sub>SCM</sub> derives primarily from studies of virus-specific CD8<sup>+</sup> T<sub>SCM</sub>. We aimed to determine if infection with Mycobacterium tuberculosis (M. tb), the etiological agent of tuberculosis, generates antigen-specific CD4<sup>+</sup> T<sub>SCM</sub> and to characterize their functional ontology.</p>Methods<p>We studied T cell responses to natural M. tb infection in a longitudinal adolescent cohort of recent QuantiFERON-TB Gold (QFT) converters and three cross-sectional QFT<sup>+</sup> adult cohorts; and to bacillus Calmette–Guerin (BCG) vaccination in infants. M. tb and/or BCG-specific CD4 T cells were detected by flow cytometry using major histocompatibility complex class II tetramers bearing Ag85, CFP-10, or ESAT-6 peptides, or by intracellular cytokine staining. Transcriptomic analyses of M. tb-specific tetramer<sup>+</sup> CD4<sup>+</sup> T<sub>SCM</sub> (CD45RA<sup>+</sup> CCR7<sup>+</sup> CD27<sup>+</sup>) were performed by microfluidic qRT-PCR, and functional and phenotypic characteristics were confirmed by measuring expression of chemokine receptors, cytotoxic molecules and cytokines using flow cytometry.</p>Results<p>M. tb-specific T<sub>SCM</sub> were not detected in QFT-negative persons. After QFT conversion frequencies of T<sub>SCM</sub> increased to measurable levels and remained detectable thereafter, suggesting that primary M. tb infection induces T<sub>SCM</sub> cells. Gene expression (GE) profiling of tetramer<sup>+</sup> T<sub>SCM</sub> showed that these cells were distinct from bulk CD4<sup>+</sup> naïve T cells (T<sub>N</sub>) and shared features of bulk T<sub>SCM</sub> and M. tb-specific tetramer<sup>+</sup> T<sub>CM</sub> and T<sub>EFF</sub> cells. These T<sub>SCM</sub> were predominantly CD95<sup>+</sup> and CXCR3<sup>+</sup>, markers typical of CD8<sup>+</sup> T<sub>SCM</sub>. Tetramer<sup>+</sup> T<sub>SCM</sub> expressed significantly higher protein levels of CCR5, CCR6, CXCR3, granzyme A, granzyme K, and granulysin than bulk T<sub>N</sub> and T<sub>SCM</sub> cells. M. tb-specific T<sub>SCM</sub> were also functional, producing IL-2, IFN-γ, and TNF-α upon antigen stimulation, and their frequencies correlated positively with long-term BCG-specific CD4<sup>+</sup> T cell proliferative potential after infant vaccination.</p>Conclusion<p>Human infection with M. tb induced distinct, antigen-specific CD4<sup>+</sup> T<sub>SCM</sub> cells endowed with effector functions, including expression of cytotoxic molecules and Th1 cytokines, and displayed chemokine receptor profiles consistent with memory Th1/17 cells. Induction of CD4<sup>+</sup> T<sub>SCM</sub> should be considered for vaccination approaches that aim to generate long-lived memory T cells against M. tb.</p> TSCM;Mycobacterium tuberculosis;memory T cells;QuantiFERON conversion;LTBI 2018-03-01
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10.3389/fimmu.2018.00324.s013