Th1 differentiation drives the accumulation of intravascular, non-protective CD4 T cells during tuberculosis

Abstract

Abstract Mycobacterium tuberculosis (Mtb) is the leading cause of death by infectious disease worldwide. The development of novel TB vaccination strategies would have dramatic global public health benefits, but have been hindered by an incomplete understanding of the mechanisms of protective immunity against Mtb infection. Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. We have shown that less-differentiated CXCR3+T-betdim Th1 cells migrate into the lung, expand and control Mtb infection after transfer into infected recipients, while KLRG1+CX3CR1+T-bethigh terminal effectors poorly migrate into the lung, fail to expand and cannot transfer protection against Mtb infection. IL-12/23p40 and T-bet have been shown to promote terminal differentiation, leading to the hypothesis that these host protective factors may have unrecognized detrimental effects on the quality of the Mtb-specific CD4 T cell response. We find IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL-12/23p40 and T-bet are also essential for the production of a subset of intravascular CX3CR1+KLRG1+Th1 cells. Furthermore, T-bet potently suppresses the development of CD69+CD103+ tissue resident phenotype effectors in the lung. In contrast, CD4 T cell-derived IFNγ inhibits the accumulation of intravascular CX3CR1+KLRG1+Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating a functional dichotomy of Th1 polarization in tuberculosis.