Suppressors of cytokine signaling inhibit effector T cell responses during Mycobacterium tuberculosis infection

Immunol Cell Biol. 2011 Oct;89(7):786-91. doi: 10.1038/icb.2011.1. Epub 2011 May 3.

Abstract

Protective immune responses during Mycobacterium tuberculosis (M. tuberculosis) infection are regulated at multiple levels and critically dependent on the balance in the secretion of pro-inflammatory and regulatory cytokines. A key factor that governs this balance at the cellular level is suppressors of cytokine signaling (SOCS). We recently demonstrated that toll-like receptor 2 and dendritic cell (DC)-SIGNR1 differentially regulate SOCS1 expression in DCs during M. tuberculosis infection. This consecutively regulated IL-12 production and determined M. tuberculosis survival. In this study, we characterized the role of SOCS1 in regulating effector responses from CD4(+) and CD8(+) T cells during M. tuberculosis infection. Our data indicate that T cells from M. tuberculosis-infected mice show increased and differential association of SOCS1 with CD3 and CD28, when compared with uninfected mice. While SOCS1 displays increased association with CD3 than CD28 in CD4(+) T cells; SOCS1 is associated more with CD28 than CD3 in CD8(+) T cells. Further, SOCS1 shows increased association with IL-12 and IL-2 receptors in both CD4(+) and CD8(+) T cells from infected mice when compared with naive mice. Silencing SOCS1 in T cells increased signal transduction from T cell receptor (TCR) and CD28 with enhanced activation of key signaling molecules and proliferation. Significantly, SOCS1-silenced T cells mediated enhanced clearance of M. tuberculosis inside macrophages. Finally, adoptive transfer of SOCS1-silenced T cells in M. tuberculosis-infected mice mediated significant reduction in M. tuberculosis loads in spleen. These results exemplify the negative role played by SOCS1 during T cell priming and effector functions during M. tuberculosis infection.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD28 Antigens / analysis
  • CD3 Complex / analysis
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Adhesion Molecules / metabolism
  • Cytokines / antagonists & inhibitors
  • Cytokines / metabolism*
  • Female
  • Interleukin-12 / biosynthesis
  • Interleukin-12 / immunology
  • Interleukin-12 / metabolism
  • Interleukin-2 / immunology
  • Interleukin-2 / metabolism
  • Lectins, C-Type / metabolism
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mycobacterium tuberculosis / immunology*
  • RNA Interference
  • RNA, Small Interfering
  • Receptors, Cell Surface / metabolism
  • Receptors, Interleukin-12 / metabolism
  • Receptors, Interleukin-2 / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism*
  • Toll-Like Receptor 2 / metabolism
  • Tuberculosis / immunology*
  • Tuberculosis / metabolism

Substances

  • CD28 Antigens
  • CD3 Complex
  • Cell Adhesion Molecules
  • Cytokines
  • DC-specific ICAM-3 grabbing nonintegrin
  • Interleukin-2
  • Lectins, C-Type
  • RNA, Small Interfering
  • Receptors, Cell Surface
  • Receptors, Interleukin-12
  • Receptors, Interleukin-2
  • Socs1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2
  • Interleukin-12