Highly Autoproliferative T Cells Specific for 60-kDa Heat Shock Protein Produce IL-4/IL-10 and IFN-γ and Are Protective in Adjuvant Arthritis

Abstract

Previously we have shown that T cell responses to the mycobacterial 60-kDa heat shock protein (hsp60) peptide M256–270 mediated protection against adjuvant arthritis in Lewis rats. We have demonstrated now that M256–270-primed T cells become highly reactive to naive syngeneic APC upon repetitive restimulation in vitro with peptide M256–265, comprising the conserved core of peptide M256–270. These autoproliferative responses in the absence of added Ag were MHC class II restricted and resulted in the production of IL-4/IL-10 and IFN-γ. Enhanced autoproliferation and expression of the cell surface molecule B7.2 by these T cells were observed in response to syngeneic heat-shocked APC, which indicated that the autoproliferation and expression of B7.2 resulted from the recognition of endogenously expressed and processed hsp. Despite their strong autoreactivity, upon transfer such T cells were found to induce a significant disease reduction in adjuvant arthritis. In contrast, T cells both primed and restimulated with peptide M256–270 became unresponsive toward syngeneic APC as well as toward the conserved core peptide M256–265, and they were devoid of protective capacity. This study demonstrates that the loss of self-tolerance toward hsp60 does not necessarily lead to autoimmune disease, but that hsp60-specific self-reactive and autoproliferative T cells may mediate T cell regulation in arthritis.

Induction of FOXP3‐expressing regulatory CD4pos T cells by human mature autologous dendritic cells

“…Although the precise nature of the peptide(s) recognized by T cells in this setting is unknown, it was previously established that MHC class II molecules bind self peptides in absence of exogenous antigens [9] and that expansion of self-reactive MHC class II-restricted T cells is driven by auto-antigens derived from apoptotic cells present in the coculture [10;11]. The fact that regulatory T cells generated during the autologous reaction proliferated and produced cyto- kines of the effector type is consistent with several recent observations [23][24][25][26][27].…”

Hsp70 expression and induction as a readout for detection of immune modulatory components in food

“…While addressing hybridoma recognition of the endogenous Hsp70, we found that some of the hybridoma clones were increasingly activated after incubation with HS APC. In line with these data, our previous study in rats showed that Hsp60-specific Tcells recognized up-regulation of cellular Hsp60 in the APC (Paul et al 2000). The mC1b peptide from mouse HspA1A has been frequently eluted from MHC class II (Halder et al 1997;Chicz et al 1993;Dengjel et al 2005).…”

DNA Fragments of the Human 60-kDa Heat Shock Protein (HSP60) Vaccinate Against Adjuvant Arthritis: Identification of a Regulatory HSP60 Peptide

“…IL-10 and TGF␤1 are immunomodulatory cytokines capable of inhibiting experimental arthritis (21)(22)(23). Indeed, T cells reactive with self-HSP60 have been previously shown to control AA (24). Inflammation up-regulates HSP60 expression in lymphocytes (25), macrophages (26), and synovial cells (27,28).…”