The Journal of Experimental Medicine
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Published 21 February 2006. doi:10.1084/jem.20051519
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 2, 461-471
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ARTICLE

 Regulation of peripheral T cell activation by calreticulin

Simona Porcellini1, Elisabetta Traggiai1, Ursula Schenk1, Denise Ferrera1, Michela Matteoli2, Antonio Lanzavecchia1, Marek Michalak3, and Fabio Grassi1

1 Institute for Research in Biomedicine, CH-6500 Bellinzona, Switzerland
2 Department of Medical Pharmacology, CNR Institute of Neuroscience, Cellular and Molecular Pharmacology, Center of Excellence for Neurodegenerative Diseases, 20129 Milano, Italy
3 Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada

CORRESPONDENCE Fabio Grassi: fabio.grassi{at}irb.unisi.ch

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.

Abbreviations used: [Ca2+]i, intracellular free Ca2+; CRT, calreticulin; DKO, double knockout; DP, double positive; FLP, fetal liver hemopoietic progenitor; MAPK, mitogen-activated protein kinase; OVAp, OVA peptide; SERCA, sarco-endoplasmic reticulum calcium transport ATPase; SP, single positive; T reg, T regulatory.


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