Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection.
journal contributionposted on 05.04.2016, 09:26 by E. Torrado, J. J. Fountain, M. Liao, M. Tighe, W. W. Reiley, R. P. Lai, G. Meintjes, John E. Pearl, X. Chen, D. E. Zak, E. G. Thompson, A. Aderem, N. Ghilardi, A. Solache, K. K. McKinstry, T. M. Strutt, R. J. Wilkinson, S. L. Swain, A. M. Cooper
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.
CitationJournal of Experimental Medicine, 2015, 212 (9), pp. 1449-1463
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Infection, Immunity and Inflammation
VersionVoR (Version of Record)
Published inJournal of Experimental Medicine
PublisherRockefeller University Press
AdultAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteCD4-Positive T-LymphocytesFemaleHumansInterleukin-7 Receptor alpha SubunitInterleukinsLectins, C-TypeMaleMiceMice, KnockoutMycobacterium tuberculosisProgrammed Cell Death 1 ReceptorReceptors, CytokineReceptors, ImmunologicReceptors, InterleukinTrans-ActivatorsTuberculosis