Host resistance to pulmonary Mycobacterium tuberculosis infection requires CD153 expression

Abstract

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 worldwide. 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 protection. However, IFNγ responses do not correlate with host protection, and several reports demonstrate that additional anti-tuberculosis CD4 T-cell effector functions remain unaccounted for. 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 (T1) cells in the lung tissue parenchyma, but its induction does not require T1 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.

Disease extent and anti‐tubercular treatment response correlates with Mycobacterium tuberculosis‐specific CD4 T‐cell phenotype regardless of HIV‐1 status

“…HLA-DR expression on these cells displayed the strongest association with systemic inflammation (defined using plasma CRP concentration) and high bacterial burden (inferred by the Xpert cycle threshold), while CD153 expression on Mtb-specific IFNc + CD4 T cells negatively associated with bacterial burden. Two recent publications have highlighted the potential role of CD153 for Mtb protection in murine and non-human primate Mtb-infection models 42 and in a non-human primate model of intravenous BCG vaccination. 43 However, at this stage, we cannot infer whether the Mtb-specific CD4 T-cell profile is a cause or a consequence of TB disease activity.…”

Prevention of tuberculosis in macaques after intravenous BCG immunization

“…Differential gene expression analysis, comparing T cells positive and negative for module 2 ( Fig. 1h and Supplementary Table 4), showed enrichment of genes previously associated with protection against TB including IFNG, TBX21, RORC, TNFSF8 25 and IL21R 26 .…”

Functionally overlapping variants control TB susceptibility in Collaborative Cross mice

“…Despite being relatively resistant to Mtb infection, CAST mice do not produce detectable levels of IFN γ in the lung (37). This observation is one of many indicating that IFN γ -independent immune mechanisms play an important protective role, particularly in the lungs (38, 45, 46). Tip1 , and Tip 3, are likely related to the IFN γ -deficient phenotype of CAST mice.…”