CD4 T Cell-Derived IFN-γ Plays a Minimal Role in Control of Pulmonary Mycobacterium tuberculosis Infection and Must Be Actively Repressed by PD-1 to Prevent Lethal Disease

PLoS Pathogens

Howard A. Young¹  Arlene H. Sharpe²  Vitaly V. Ganusov³  Keith D. Kauffman⁴  Michelle A. Sallin⁴  Shunsuke Sakai⁴  Daniel L. Barber⁴ 

[1] Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland, United States of America;Department of Microbiology and Immunobiology, and Evergrande Center for Immunological Diseases, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts, United States of America;Department of Microbiology, University of Tennessee, Knoxville, Tennessee, United States of America;T lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America

关键词: T helper cells;    Mycobacterium tuberculosis;    Spleen;    T cells;    Tuberculosis;    Infectious disease control;    Cell staining;    Cytokines;   

DOI  :  10.1371/journal.ppat.1005667

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

IFN-γ–producing CD4 T cells are required for protection against Mycobacterium tuberculosis (Mtb) infection, but the extent to which IFN-γ contributes to overall CD4 T cell-mediated protection remains unclear. Furthermore, it is not known if increasing IFN-γ production by CD4 T cells is desirable in Mtb infection. Here we show that IFN-γ accounts for only ~30% of CD4 T cell-dependent cumulative bacterial control in the lungs over the first six weeks of infection, but >80% of control in the spleen. Moreover, increasing the IFN-γ–producing capacity of CD4 T cells by ~2 fold exacerbates lung infection and leads to the early death of the host, despite enhancing control in the spleen. In addition, we show that the inhibitory receptor PD-1 facilitates host resistance to Mtb by preventing the detrimental over-production of IFN-γ by CD4 T cells. Specifically, PD-1 suppressed the parenchymal accumulation of and pathogenic IFN-γ production by the CXCR3+KLRG1-CX3CR1- subset of lung-homing CD4 T cells that otherwise mediates control of Mtb infection. Therefore, the primary role for T cell-derived IFN-γ in Mtb infection is at extra-pulmonary sites, and the host-protective subset of CD4 T cells requires negative regulation of IFN-γ production by PD-1 to prevent lethal immune-mediated pathology.

【 授权许可】

CC BY