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

Egidio Torrado; Jeffrey J Fountain; Mingfeng Liao; Michael Tighe; William W Reiley; Rachel P Lai; Graeme Meintjes; John E Pearl; Xinchun Chen; Daniel E Zak; Ethan G Thompson; Alan Aderem; Nico Ghilardi; Alejandra Solache; K Kai McKinstry; Tara M Strutt; Robert J Wilkinson; Susan L Swain; Andrea M Cooper

doi:10.1084/jem.20141520

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

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

Authors

Egidio Torrado¹, Jeffrey J Fountain¹, Mingfeng Liao², Michael Tighe¹, William W Reiley¹, Rachel P Lai³, Graeme Meintjes⁴, John E Pearl¹, Xinchun Chen⁵, Daniel E Zak⁶, Ethan G Thompson⁶, Alan Aderem⁶, Nico Ghilardi⁷, Alejandra Solache¹, K Kai McKinstry⁸, Tara M Strutt⁸, Robert J Wilkinson⁹, Susan L Swain⁸, Andrea M Cooper¹⁰

Affiliations

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.

Publication types

Clinical Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Antigens, CD / genetics
Antigens, CD / immunology
Antigens, Differentiation, T-Lymphocyte / genetics
Antigens, Differentiation, T-Lymphocyte / immunology
CD4-Positive T-Lymphocytes / immunology*
CD4-Positive T-Lymphocytes / pathology
Female
Humans
Interleukin-7 Receptor alpha Subunit / genetics
Interleukin-7 Receptor alpha Subunit / immunology
Interleukins / genetics
Interleukins / immunology
Lectins, C-Type / genetics
Lectins, C-Type / immunology
Male
Mice
Mice, Knockout
Mycobacterium tuberculosis / immunology*
Programmed Cell Death 1 Receptor / genetics
Programmed Cell Death 1 Receptor / immunology
Receptors, Cytokine / genetics
Receptors, Cytokine / immunology*
Receptors, Immunologic / genetics
Receptors, Immunologic / immunology
Receptors, Interleukin / genetics
Receptors, Interleukin / immunology*
Trans-Activators / genetics
Trans-Activators / immunology
Tuberculosis / genetics
Tuberculosis / immunology*
Tuberculosis / pathology

Substances

Antigens, CD
Antigens, Differentiation, T-Lymphocyte
CD69 antigen
IL27RA protein, human
Il27 protein, mouse
Il27ra protein, mouse
Interleukin-7 Receptor alpha Subunit
Interleukins
KLRG1 protein, human
Klrg1 protein, mouse
Lectins, C-Type
MYDGF protein, human
PDCD1 protein, human
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor
Receptors, Cytokine
Receptors, Immunologic
Receptors, Interleukin
Trans-Activators

Abstract

Publication types

MeSH terms

Substances

Grants and funding