Cell Reports
Volume 18, Issue 13, 28 March 2017, Pages 3091-3104
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Article
Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis

https://doi.org/10.1016/j.celrep.2017.03.007Get rights and content
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Highlights

  • T-bet and p40 are dispensable for entry of CD4 T cells into the lungs in Mtb infection

  • T-bet and p40 drive production of non-protective intravascular CX3CR1+ Th1 cells

  • T-bet inhibits the generation of Trm-like CD69+CD103+ Th17 cells in Mtb infection

  • Th1-derived IFN-γ negatively regulates the accumulation of iv+CX3CR1+ Th1 cells

Summary

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-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 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.

Keywords

tuberculosis
Th1 cells
T-bet
terminal effector
T cell migration
IL-12

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