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.

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
  • IL27 protein, human
  • IL27RA protein, human
  • Il27 protein, mouse
  • Il27ra protein, mouse
  • Interleukin-7 Receptor alpha Subunit
  • Interleukins
  • KLRG1 protein, human
  • Klrg1 protein, mouse
  • Lectins, C-Type
  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Cytokine
  • Receptors, Immunologic
  • Receptors, Interleukin
  • Trans-Activators