Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and is among the top ten causes of all human deaths worldwide1. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFNγ production is the primary mechanism of CD4 T-cell-mediated protection2,3. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for4,5,6,7,8. Here we show that the tumour-necrosis factor (TNF) superfamily molecule CD153 (encoded by the gene Tnfsf8) is required for control of pulmonary Mtb infection by CD4 T cells. In Mtb-infected mice, CD153 expression is highest on Mtb-specific T helper 1 (TH1) cells in the lung tissue parenchyma, but its induction does not require TH1 cell polarization. CD153-deficient mice develop high pulmonary bacterial loads and succumb early to Mtb infection. Reconstitution of T-cell-deficient hosts with either Tnfsf8−/− or Ifng−/− CD4 T cells alone fails to rescue mice from early mortality, but reconstitution with a mixture of Tnfsf8−/− and Ifng−/− CD4 T cells provides similar protection as wild-type T cells. In Mtb-infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to blood, and the frequency of Mtb-specific CD153-expressing CD4 T cells inversely correlates with bacterial loads in granulomas. In Mtb-infected humans, CD153 defines a subset of highly polyfunctional Mtb-specific CD4 T cells that are much more abundant in individuals with controlled latent Mtb infection compared to those with active tuberculosis. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, CD153 is a major immune mediator of host protection against pulmonary Mtb infection and CD4 T cells are one important source of this molecule.
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CD4 T-cell microarray data are publicly available, accession number GSE116830. All data reported in this study are available from the corresponding author upon reasonable request.
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We thank N. Zhu for technical assistance and the animal care staff of National Institute of Allergy and Infectious Diseases (NIAID) Comparative Medicine Branch. We thank B. Hague for help with cell sorting. We thank R. Germain for helpful discussions. This work was supported by the Intramural Research Programme of NIAID/National Institutes of Health (NIH) and the NIH (5U01AI115940-04). R.J.W. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC00110218), the UK Medical Research Council (FC00110218) and Wellcome (FC00110218). R.J.W. also receives support from Wellcome (104803, 203135), NIH (U19A1111276) and the Medical Research Council of South Africa (SHIP).
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Nature Microbiology (2018)