Immunological effects of extracellular calreticulin

Abstract

A number of stress proteins, including hsp70, hsp90, gp96 and calreticulin (CRT), have been shown to elicit protective immune responses against their tumour of origin. This effect appears to be due to their ability to act as chaperones. Hsp70 and gp96 have been particularly well studied. In this study, I have investigated the antigen chaperoning and APC activating functions of the ER-resident chaperone CRT.

I have purified CRT from a murine mastocytoma cell line and removed contaminating endotoxin from this and my model antigen ovalbumin (OVA). Immunisation of mice with this CRT results in a degree of protection from challenge with the source tumour, P815. In vitro co-administration of CRT with OVA results in proliferation of adoptively transferred OVA-specific CD8⁺, but not CD4⁺ T cells. In vitro, incubation of CRT with autologous, bone marrow-derived dendritic cells (DCs) does not induce expression of activation markers or production of pro-inflammatory cytokines. CRT also had no effect on phagocytosis of latex beads by a DC line. Investigations into the effect of CRT on the ability of OVA-pulsed DCs to prime naïve OVA-specific transgenic T cells in vitro indicated that it does not enhance their ability to prime MHC Class II-restricted OVA specific T cells. However, some IL-2 production by Class I-restricted OVA-specific T cells was observed.

I have also demonstrated that CRT binds specifically to receptors on DCs and macrophages and is subsequently internalised. Preliminary data indicate that CRT can be complexed to peptides in vitro and deliver these to DCs for processing and presentation to T cells.

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