期刊
FRONTIERS IN IMMUNOLOGY
卷 9, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2018.01995
关键词
CD4 T cell; CD8 T cell; tuberculosis; PD-1; IFN-gamma; proliferation
类别
资金
- National Institute of Allergy and Infectious Diseases at the National Institutes of Health [R01AI083156, U01AI115940]
- Carnegie Corporation
- University of Cape Town
- Canada Africa Prevention Trials (CAPT) Network
- Francis Crick Institute from Cancer Research UK [FC00110218]
- Medical Research Council UK [FC00110218]
- Wellcome Trust [104803, 203135]
- MRC [MC_U117588499] Funding Source: UKRI
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P30AI050409, U01AI115940] Funding Source: NIH RePORTER
- OFFICE OF THE DIRECTOR, NATIONAL INSTITUTES OF HEALTH [P51OD011132] Funding Source: NIH RePORTER
Persistent antigen stimulation in chronic infections has been associated with antigen-specific T cell dysfunction and upregulation of inhibitory receptors, including programmed cell death protein 1 (PD-1). Pulmonary tuberculosis (TB) disease is characterized by high levels of Mycobacterium tuberculosis (Mtb), yet the relationship between bacterial load, PD-1 expression, and Mtb-specific T cell function in human TB has not been well-defined. Using peripheral blood samples from adults with LTBI and with pulmonary TB disease, we tested the hypothesis that PD-1 expression is associated with bacterial load and functional capacity ofMtb-specific T cell responses. We found that PD-1 was expressed at significantly higher levels on Th1 cytokine-producingMtb-specific CD4 T cells from patients with smear-positive TB, compared with smear-negative TB and LTBI, which decreased after completion of anti-TB treatment. By contrast, expression of PD-1 on Mtb-specific CD8 T cells was significantly lower than on Mtb-specific CD4 T cells and did not differ by Mtb infection and disease status. In vitro stimulation of PBMC with Mtb antigens demonstrated that PD-1 is induced on proliferatingMtb-specific CD4 T cells and that Th1 cytokine production capacity is preferentially maintained within PD-1+ proliferating CD4 T cells, compared with proliferating Mtb-specific CD4 T cells that lack PD-1 expression. Together, these data indicate that expression of PD-1 on Mtb-specific CD4 T cells is indicative of mycobacterial antigen exposure and identifies a population of effector cells with Th1 cytokine production capacity. These studies provide novel insights into the role of the PD-1 pathway in regulating CD4 and CD8 T cell responses in Mtb infection and provide rationale for future studies to evaluate PD-1 expression on antigen-specific CD4 T cells as a potential biomarker for bacterial load and treatment response in human TB.
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