Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection.
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.
Trudeau Institute, Saranac Lake, NY 12983.
Egidio
E
Torrado
Trudeau Institute, Saranac Lake, NY 12983.
Jeffrey J
JJ
Fountain
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.
Mingfeng
M
Liao
Trudeau Institute, Saranac Lake, NY 12983.
Michael
M
Tighe
Trudeau Institute, Saranac Lake, NY 12983.
William W
WW
Reiley
Mill Hill Laboratory, The Francis Crick Institute, London NW7 1AA, England, UK.
Rachel P
RP
Lai
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.
Graeme
G
Meintjes
Trudeau Institute, Saranac Lake, NY 12983.
John E
JE
Pearl
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.
Xinchun
X
Chen
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109.
Daniel E
DE
Zak
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109.
Ethan G
EG
Thompson
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, WA 98109.
Alan
A
Aderem
Department of Immunology, Genentech, South San Francisco, CA 94080.
Nico
N
Ghilardi
Trudeau Institute, Saranac Lake, NY 12983.
Alejandra
A
Solache
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655.
K Kai
KK
McKinstry
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655.
Tara M
TM
Strutt
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.
Robert J
RJ
Wilkinson
Department of Pathology, University of Massachusetts Medical School, Worcester, MA 01655.
Susan L
SL
Swain
Trudeau Institute, Saranac Lake, NY 12983 acooper@trudeauinstitute.org.
Andrea M
AM
Cooper
D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000276:immunology; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology; D018121:Receptors, Cytokine / Q000235:genetics / Q000276:immunology*; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology; D018123:Receptors, Interleukin / Q000235:genetics / Q000276:immunology*; D015534:Trans-Activators / Q000235:genetics / Q000276:immunology; D014376:Tuberculosis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053699:Interleukin-7 Receptor alpha Subunit; D007378:Interleukins; D037181:Lectins, C-Type; D061026:Programmed Cell Death 1 Receptor; D018121:Receptors, Cytokine; D011971:Receptors, Immunologic; D018123:Receptors, Interleukin; D015534:Trans-Activators; D000099192:CD69 Antigens; C112441:IL27RA protein, human; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; C113413:KLRG1 protein, human; C451496:Klrg1 protein, mouse; C464565:MYDGF protein, human; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse