Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo

Speaker: 楊育靜

Time: 14:00-15:00 02/25/2004

Commentator: 謝奇璋 醫師

Place: Room 601

Abstract

Professional antigen-presenting cells (APCs), most notably DCs, play a key role in initiating the immune response. DCs provide a direct link between innate and adaptive immunity¹. DCs can also induce antigen-specific unresponsiveness or tolerance². However, the molecular mechanisms that dictate whether activation or tolerance are induced after T cell–APC interaction remain poorly understood. The APC maturation signals that convert tolerogenic antigen presentation into activation of immunity are being increasingly well characterized. Heat shock protein 70 (Hsp70) has recently been shown to exert cytokine-like effects on APC maturation³. Such finding reinforces the possibility that Hsp may serve as endogenous signals for APC maturation, and may have a role in the regulation of immunity versus tolerance. To determine whether mammalian Hsp70 can influence the immune responses to antigens in vivo, the authors examined the effects of Hsp70 on the induction of autoimmunity in a lymphocytic choriomeningitis virus glycoprotein (LCMV-GP) model of autoimmune diabetes. LCMV-GP is expressed in pancreatic islet β-cells under the control of rat insulin promoter (RIP-GP). The TCR transgenic mice that have CD8⁺ T cells expressing the LCMV-GP–specific T cell receptor (P14 TCR) were mated to generate double-transgenic mice (RIP-GP/P14 TCR) to assess the requirements for the induction of autoimmunity⁴. This paper show that administration of gp33 alone, the immunodominant epitope consisting of amino acids 33–41 of LCMV-GP, induces tolerance of P14 TCR T cells and does not lead to diabetes in RIP-GP/P14 TCR mice. However, coadministration of Hsp70 and gp33 stimulates the responses of cytotoxic T-lymphocyte and promotes IL-12 production by DCs through a CD40-dependent mechanism. These will result in autoimmune diabetes in RIP-GP/P14 TCR mice. These results indicate that the Hsp70, a necrotic cell associated endogenous signal, can promote autoimmune response. These findings also reveal how therapies might be developed to specifically target autoimmune processes while bypassing other immune response necessary for host defence⁵.

References

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2. Steinman, R.M. et al. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).

3. Asea, A. et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat. Med. 6, 435–442 (2000).

4. Garza, K.M. et al. Role of antigen-presenting cells in mediating tolerance and autoimmunity. J. Exp. Med. 191, 2021–2027 (2000).

5. Millar, D.G. et al. Hsp70 promotes antigen-presenting cell function and converts T-cell tolerance to autoimmunity in vivo. Nat. Med. 9, 1469–1476 (2003).