jem_20141520.pdf (2.19 MB)
Interleukin 27R regulates CD4+ T cell phenotype and impacts protective immunity during Mycobacterium tuberculosis infection
journal contributionposted on 2020-09-18, 13:42 authored by 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
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.
AdultAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteCD4-Positive T-LymphocytesFemaleHumansInterleukin-7 Receptor alpha SubunitInterleukinsLectins, C-TypeMaleMiceMice, KnockoutMycobacterium tuberculosisProgrammed Cell Death 1 ReceptorReceptors, CytokineReceptors, ImmunologicReceptors, InterleukinTrans-ActivatorsTuberculosisWilkinson, R U11758849911 Medical and Health SciencesImmunology