Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): Michelle A. Sallin, Shunsuke Sakai, Keith D. Kauffman, Howard A. Young, Jinfang Zhu, Daniel L. Barber
Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73⁺CXCR3⁺T-bet^dim 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 prominent subset of intravascular CX3CR1⁺KLRG1⁺ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69⁺CD103⁺ tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-γ 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 the dual nature of Th1 polarization in tuberculosis.

Graphical abstract

Teaser

Sallin et al. show that IL-12/23p40 and T-bet have a detrimental impact on the quality of some Th1 cells in TB. Although required for IFN-γ production and host survival, these factors are dispensable for migration of T cells into the lung and drive the differentiation of non-protective intravascular CX3CR1⁺KLRG1⁺ Th1 cells.


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