Mycobacterium tuberculosis (Mtb)-specific CD4 T cells differentiate into protective lung parenchyma-homing and non-protective intravascular subsets, but the signals that instruct these fates are poorly understood. Here we show that CD28 co-stimulation regulates host protection during Mtb infection. Cd28-/- mice are susceptible to Mtb infection, displaying higher bacterial loads and reduced survival compared to wild type mice. Cd28-/- Mtb-specific T cells expand normally but are skewed towards the lung intravascular phenotype. CD4 T cells primed in the absence of CD28 co-stimulation in B7 deficient hosts are unable to confer protection upon adoptive transfer into B7WT Mtb-infected T cell deficient mice, despite restoration of CD28:B7 signaling in the recipients. B7-1/2 expression by infected lung macrophages is not required for bacterial control, suggesting that B7:CD28 interactions in the T cell priming phase are required for host protection. In contrast to CD28 deficiency, lack of CTLA-4 increases lung parenchymal Mtb-specific CD4 T cell responses. However, CTLA-4 is required on both effector and Treg cells to limit detrimental host responses during Mtb infection. These findings show that the B7/CD28/CTLA-4 axis is central to host protection in Mtb infection, as it drives differentiation of protective T cells and limits detrimental inflammation by otherwise protective T cells.
