T-cell-specific deletion of STIM1 and STIM2 protects mice from EAE by impairing the effector functions of Th1 and Th17 cells

Eur J Immunol. 2010 Nov;40(11):3028-42. doi: 10.1002/eji.201040614. Epub 2010 Oct 27.

Abstract

T-cell function is dependent on store-operated Ca(2+) influx that is activated by the stromal interaction molecules (STIM) 1 and 2. We show that mice with T-cell-specific deletion of STIM1 or STIM2 are protected from EAE, a mouse model of multiple sclerosis (MS). While STIM1- and STIM2-deficient T cells could be successfully primed by autoantigen, they failed to produce the proinflammatory cytokines IL-17 and IFN-γ. STIM1-deficient T cells showed reduced expression of IL-23R, required for Th17 cell homeostasis, and had impaired chemokine-dependent T-cell migration caused by a lack of chemokine-induced Ca(2+) influx. Autoantigen-specific STIM1- or STIM2-deficient T cells failed to expand and accumulate in the CNS and lymph nodes following adoptive transfer to passively induce EAE, suggesting that autoantigen-specific restimulation or homeostasis of STIM1- and STIM2-deficient T cells are impaired. Combined deletion of both STIM1 and STIM2, previously shown to impair Treg development and function, completely protected mice from EAE. This indicates that, in the absence of Ca(2+) influx, autoreactive T cells are severely dysfunctional rendering Treg dispensable for the prevention of CNS inflammation. Our findings demonstrate that both STIM1 and STIM2 are critical for T-cell function and autoimmunity in vivo.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / immunology
  • Calcium / metabolism
  • Calcium Channels
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Encephalomyelitis, Autoimmune, Experimental / genetics
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Gene Deletion
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / metabolism
  • Multiple Sclerosis / pathology
  • Receptors, Interleukin / biosynthesis
  • Receptors, Interleukin / genetics
  • Receptors, Interleukin / immunology
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • T-Lymphocytes, Regulatory / pathology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th1 Cells / pathology
  • Th17 Cells / immunology*
  • Th17 Cells / metabolism
  • Th17 Cells / pathology

Substances

  • Calcium Channels
  • Membrane Glycoproteins
  • Receptors, Interleukin
  • Stim1 protein, mouse
  • Stim2 protein, mouse
  • Stromal Interaction Molecule 1
  • Stromal Interaction Molecule 2
  • interleukin-23 receptor, mouse
  • Calcium