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J Exp Med. 2015 Aug 24;212(9):1449-63. doi: 10.1084/jem.20141520. Epub 2015 Aug 17.

Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection.

Author information

1
Trudeau Institute, Saranac Lake, NY 12983.
2
Trudeau Institute, Saranac Lake, NY 12983 Guangdong Key Laboratory for Emerging Infectious Disease and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen 518112, China Guangdong Key Laboratory for Emerging Infectious Disease and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen 518112, China.
3
Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, England, UK.
4
Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, Cape Town, South Africa Department of Medicine, Imperial College London, London SW7 2AZ, England, UK.
5
Guangdong Key Laboratory for Emerging Infectious Disease and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen 518112, China Guangdong Key Laboratory for Emerging Infectious Disease and Shenzhen Key Laboratory of Infection and Immunity, Shenzhen Third People's Hospital, Guangdong Medical College, Shenzhen 518112, China.
6
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109.
7
Department of Immunology, Genentech, South San Francisco, CA 94080.
8
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655.
9
Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, England, UK Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, Cape Town, South Africa Department of Medicine, Imperial College London, London SW7 2AZ, England, UK.
10
Trudeau Institute, Saranac Lake, NY 12983 acooper@trudeauinstitute.org.

Abstract

CD4+ T cells mediate protection against Mycobacterium tuberculosis (Mtb); however, the phenotype of protective T cells is undefined, thereby confounding vaccination efforts. IL-27 is highly expressed during human tuberculosis (TB), and absence of IL-27R (Il27ra) specifically on T cells results in increased protection. IL-27R deficiency during chronic Mtb infection does not impact antigen-specific CD4+ T cell number but maintains programmed death-1 (PD-1), CD69, and CD127 expression while reducing T-bet and killer cell lectin-like receptor G1 (KLRG1) expression. Furthermore, T-bet haploinsufficiency results in failure to generate KLRG1+, antigen-specific CD4+ T cells, and in improved protection. T cells in Il27ra(-/-) mice accumulate preferentially in the lung parenchyma within close proximity to Mtb, and antigen-specific CD4+ T cells lacking IL-27R are intrinsically more fit than intact T cells and maintain IL-2 production. Improved fitness of IL-27R-deficient T cells is not associated with increased proliferation but with decreased expression of cell death-associated markers. Therefore, during Mtb infection, IL-27R acts intrinsically on T cells to limit protection and reduce fitness, whereas the IL-27R-deficient environment alters the phenotype and location of T cells. The significant expression of IL-27 in TB and the negative influence of IL-27R on T cell function demonstrate the pathway by which this cytokine/receptor pair is detrimental in TB.

PMID:
26282876
PMCID:
PMC4548054
DOI:
10.1084/jem.20141520
[Indexed for MEDLINE]
Free PMC Article

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