CD153 expression by CD4 T cells is required for control of pulmonary Mycobacterium tuberculosis infection

ABSTRACT: Mycobacterium tuberculosis infection (Mtb) is the leading cause of death due to a single infectious agent and among the top ten causes of all human death worldwide1. CD4 T cells are essential for resistance to Mtb infection, and for decades it has been thought that IFN production is the primary mechanism of CD4 T cell-mediated protection2,3. However, IFN responses do not correlate with host protection, and several reports have demonstrated that additional anti-tuberculous CD4 T cell effector functions remain unaccounted for4-8. Here we show that the TNF superfamily molecule CD153 (TNFSF8) is required for IFN-independent control of pulmonary Mtb infection by CD4 T cells. In Mtb infected mice, CD153 expression is highest on Ag-specific Th1 cells in the lung tissue parenchyma, but its induction does not require Th1 polarization. CD153 deficient mice develop high pulmonary but not splenic bacterial loads and succumb early to Mtb infection. Reconstitution of T cell-deficient hosts with either CD153-/- or IFN-/- CD4 T cells fails to rescue mice from early mortality, but reconstitution with a mixture of CD153-/- and IFN-/- CD4 T cells provides similar protection as WT T cells. In Mtb infected non-human primates, CD153 expression is much higher on Ag-specific CD4 T cells in the airways compared to the 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 TB. In all three species, Mtb-specific CD8 T cells did not upregulate CD153 following peptide stimulation. Thus, we have identified expression of CD153 by CD4 T cells as a major immune mechanism of host protection against pulmonary Mtb infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE116830 | GEO | 2018/07/10

REPOSITORIES: GEO