ABSTRACT
The development of a highly effective tuberculosis (TB) vaccine is likely dependent on our understanding of what constitutes a protective immune response to TB. Accumulating evidence suggests that CD4+ T cells producing IL-22, a distinct subset termed ‘Th22’ cells, may contribute to protective immunity to TB. Thus, we characterized Mycobacterium tuberculosis (Mtb)-specific Th22 (and Th1 and Th17) cells in 72 individuals with latent tuberculosis infection (LTBI) or TB disease, with and without human immunodeficiency virus (HIV)-1 infection. We investigated the functional properties (IFN-γ, IL-22 and IL-17 production), memory differentiation (CD45RA, CD27 and CCR7) and activation profile (HLA-DR) of Mtb-specific CD4+ T cells. In HIV-uninfected individuals with LTBI, we detected abundant IFN-γ producing CD4+ T cells (median: 0.93%) and IL-22-producing CD4+ T cells (median: 0.46%) in response to Mtb. The frequency of IL-17 producing CD4+ T cells was much lower, at a median of 0.06%. Consistent with previous studies, IL-22 was produced by a distinct subset of CD4+ T cells and not co-expressed with IL-17. Mtb-specific IL-22 responses were markedly reduced (median: 0.08%) in individuals with TB disease and HIV co-infection compared to IFN-γ responses. Mtb-specific Th22 cells exhibited a distinct memory and activation phenotype compared to Th1 and Th17 cells. Furthermore, Mtb-specific IL-22 was produced by conventional CD4+ T cells that required T cell receptor (TCR) engagement. In conclusion, we confirm that Th22 cells contribute substantially to the immune response to TB. Depletion of Mtb-specific Th22 cells during HIV co-infection may contribute to increased risk of TB disease.
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This project is part of the EDCTP2 programme supported by the European Union (EU)'s Horizon 2020 programme (TMA2016SF-1535-CaTCH-22, to WAB). WAB was also funded by the SAMRC, NRF SA (92755) and NHLS Trust (2016-2DEV04). Further funding came from the National Institutes of Health, the Office of the Director (OD) (NIH, R21AI115977 to CR). CR is supported by the EDCTP programme supported by the European Union's Horizon 2020 programme (TMA2017SF-1951-TB-Spec, to CR). RJW is supported by the Wellcome Trust (203135 and 104803), NIH (U01 AI115940), the Francis Crick Institute (Cancer Research UK, MRC UK and Wellcome FC0010218), and SAMRC (SHIP). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.
Yes
The details of the IRB/oversight body that provided approval or exemption for the research described are given below:
These studies were approved by the University of Cape Town, Faculty of Health Sciences Human Research Ethics Committee (HREC 279/2012 and HREC 896/2014).
All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.
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Footnotes
Author order corrected
Data Availability
All data generated or analysed during this study are available from the corresponding author (WAB) on reasonable request.
Data Availability
All the reported data are available within the manuscript