Regulation of peripheral T cell activation by calreticulin

J Exp Med. 2006 Feb 20;203(2):461-71. doi: 10.1084/jem.20051519.

Abstract

Regulated expression of positive and negative regulatory factors controls the extent and duration of T cell adaptive immune response preserving the organism's integrity. Calreticulin (CRT) is a major Ca2+ buffering chaperone in the lumen of the endoplasmic reticulum. Here we investigated the impact of CRT deficiency on T cell function in immunodeficient mice reconstituted with fetal liver crt-/- hemopoietic progenitors. These chimeric mice displayed severe immunopathological traits, which correlated with a lower threshold of T cell receptor (TCR) activation and exaggerated peripheral T cell response to antigen with enhanced secretion of inflammatory cytokines. In crt-/- T cells TCR stimulation induced pulsatile cytosolic elevations of Ca2+ concentration and protracted accumulation of nuclear factor of activated T cells in the nucleus as well as sustained activation of the mitogen-activated protein kinase pathways. These observations support the hypothesis that CRT-dependent shaping of Ca2+ signaling critically contributes to the modulation of the T cell adaptive immune response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calreticulin / deficiency
  • Calreticulin / genetics
  • Calreticulin / physiology*
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Clonal Anergy / genetics
  • Clonal Anergy / immunology
  • Female
  • Immunologic Memory / genetics
  • Liver / immunology
  • Liver / pathology
  • Lymphocyte Activation* / genetics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Radiation Chimera / immunology
  • Signal Transduction / genetics
  • Signal Transduction / immunology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes, Regulatory / immunology
  • Thymus Gland / immunology
  • Thymus Gland / metabolism
  • Thymus Gland / pathology

Substances

  • Calreticulin