Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis.
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 T(h)1 to T(h)2 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-1alpha 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 beta cells by signaling in concert both innate and adaptive receptors on T cells.
Nussbaum
Gabriel
G
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Zanin-Zhorov
Alexandra
A
Quintana
Francisco
F
Lider
Ofer
O
Cohen
Irun R
IR
D019264:Adoptive Transfer / Q000379:methods; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018834:Chaperonin 60; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology* / Q000517:prevention & control; D005260:Female; D006360:Heat-Shock Proteins / Q000276:immunology / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D014611:Vaccination / Q000379:methods
D018834:Chaperonin 60; D006360:Heat-Shock Proteins; D010446:Peptide Fragments; C095402:peptide 277, heat shock protein 60