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Front. Immunol. | doi: 10.3389/fimmu.2018.00324

FUNCTIONAL, ANTIGEN-SPECIFIC STEM CELL MEMORY (TSCM) CD4+ T CELLS ARE INDUCED BY HUMAN M. TUBERCULOSIS INFECTION

  • 1Pathology, University of Cape Town, South Africa

BACKGROUND: Maintenance of long lasting immunity is thought to depend on stem cell memory T cells (TSCM), which have superior self-renewing capacity, longevity and proliferative potential compared with central memory (TCM) or effector (TEFF) T cells. Our knowledge of TSCM derives primarily from studies of virus-specific CD8+ TSCM. We aimed to determine if infection with Mycobacterium tuberculosis (M.tb), the etiological agent of tuberculosis, generates antigen-specific CD4+ TSCM and to characterise their functional ontology.

METHODS: 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+ 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 MHC-class II tetramers bearing Ag85, CFP-10 or ESAT-6 peptides, or by intracellular cytokine staining. Transcriptomic analyses of M.tb-specific tetramer+ CD4+ TSCM (CD45RA+CCR7+CD27+) 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.

RESULTS: M.tb-specific TSCM were not detected in QFT-negative persons. After QFT conversion frequencies of TSCM increased to measurable levels and remained detectable thereafter, suggesting that primary M.tb infection induces TSCM cells. Gene expression profiling of tetramer+ TSCM showed that these cells were distinct from bulk CD4+ naïve T cells (TN) and shared features of bulk TSCM and M.tb-specific tetramer+ TCM and TEFF cells. These TSCM were predominantly CD95+ and CXCR3+, markers typical of CD8+ TSCM. Tetramer+ TSCM expressed significantly higher protein levels of CCR5, CCR6, CXCR3, Granzyme A, Granzyme K and Granulysin than bulk TN and TSCM cells. M.tb-specific TSCM 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+ T cell proliferative potential after infant vaccination.

CONCLUSIONS: Human infection with M.tb induced distinct, antigen-specific CD4+ TSCM 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+ TSCM should be considered for vaccination approaches that aim to generate long-lived memory T cells against M.tb.

Keywords: TSCM, Mycobacterium tuberculosis, memory T cells, Quantiferon conversion, LTBI

Received: 21 Dec 2017; Accepted: 06 Feb 2018.

Edited by:

Jesús Gonzalo-Asensio, University of Zaragoza, Spain

Reviewed by:

Enrico Lugli, National Institutes of Health (NIH), United States
Ian Orme, Colorado State University, United States  

Copyright: © 2018 Mpande, Dintwe, Musvosvi, Mabwe, Bilek, Hatherill, Nemes and Scriba. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Thomas J. Scriba, University of Cape Town, Pathology, Anzio Road, Observatory, Cape Town, 7925, South Africa, thomas.scriba@uct.ac.za