Reference Database

Calreticulin (CRT) is a Ca²⁺ binding molecular chaperone in the endoplasmic reticulum, but can also accumulate in soluble form in serum and/or synovial fluid of patients with rheumatic disorders. We have recently shown that a prokaryotically expressed recombinant CRT fragment 39-272 (rCRT/39-272) exhibited potent stimulatory activities against macrophages and B cells. However, intraperitoneal (i.p.) administration of rCRT/39-272 effectively suppressed delayed-type hypersensitivity in mice, attributable to production of anti-CRT Abs favoring Th2 cell differentiation. In this study, we further demonstrate that i.p. injection of rCRT/39-272 reduced disease severity in mouse model of experimental autoimmune encephalomyelitis (EAE), by inhibiting autoantigen-specific Th1 differentiation in vivo. Interestingly, the EAE-modulating effect of rCRT/39-272 was attributed to activation/expansion of CD1d(hi)CD5⁺ IL-10-secreting B (B10) cells rather than induction of CRT-specific antibodies in mice. In vitro, rCRT/39-272 could activate and expand murine splenic B10 cells through a Toll like receptor 4 (TLR4)-dependent pathway. The rCRT-activated B10 cells were able to not only enhance Th2 cell differentiation in vitro but also reduce EAE scores of recipient animals in passive transfer experiments. These results revealed soluble CRT, likely released by tissue cells under stress conditions, as a potentially important multi-faced player in immunoregulation and immunopathological responses.