Peptide p277 is a 24-amino acid fragment of the heat shock protein 60 molecule, first discovered to be an antigen for diabetogenic T-cell clones in non-obese diabetic (NOD) mice. Therapeutic vaccination with p277 can arrest the spontaneous diabetogenic process both in NOD mice and in humans associated with a Th1 to Th2 cytokine shift specific for the autoimmune T cells. We now report that p277 can directly signal human T cells via innate toll-like receptor (TLR)-2, leading to up-regulation of integrin-mediated adhesion to fibronectin, and inhibition of chemotaxis to the chemokine SDF-1α in vitro. Resting CD45RA+ T cells responded to lower concentrations of p277 than resting CD45RO+ T cells, but activation of CD45RO + T cells greatly increased their sensitivity to p277. Mouse T cells, but not macrophages, were also sensitive to the innate effects of peptide p277, and adoptive transfer of diabetes by splenic T cells from NOD mice could be inhibited by p277 treatment before transfer. Thus, T cells do respond innately to p277, and signaling by soluble p277 through TLR2 could contribute to the treatment of type 1 diabetes; p277 may stop the destruction of β cells by signaling in concert both innate and adaptive receptors on T cells.
Bibliographical noteFunding Information:
I.R.C. is the incumbent of the Mauerberger Chair of Immunology and the Director of the Center for the Study of Emerging Diseases, Jerusalem. G.N. was supported by a Juvenile Diabetes Research Foundation International post-doctoral fellowship.
- Delayed-type hypersensitivity
- Toll-like receptors
- Type 1 diabetes mellitus