The unique ability of the heat shock proteins (hsps) gp96 and hsp70 to evoke potent anti-tumor immunity appears to rely on two main properties: (1) their peptide-dependent capacity to chaperone and elicit adaptive CTL responses against antigenic peptides through receptor-mediated endocytosis by APCs and representation by APC's MHC classical class la molecules and (2) their peptide-independent capacity to activate APCs. Anti-tumor CTLs are thought to be the main effectors in hsp-mediated responses. However, increasing evidence suggests that NK cells and other less well-characterized cytotoxic cell types recognizing non-classical class Ib molecules may also play a critical role. Since tumors commonly down-regulate expression of MHC class la, thereby escaping immune surveillance, our observation that these hsps can generate anti-tumor immune responses that are not class la-restricted, but possibly involve class Ib molecules, clearly merits further exploration. Therefore, we propose to test the hypothesis that hsps can stimulate classical class la unrestricted CTLs (CCU-CTLs) whose effector function involves class Ib molecules. To this end, we have developed in the frog, Xenopus, a unique and versatile experimental model system characterized by minor and major histocompatibility-defined cloned animals and a MHC class la-negative transplantable thymic lymphoma. This model will be used to evaluate, by in vitro killing assays and by in vivo adoptive cell transfer and antibody depletion protocols, the ability of gp96 and hsp70 to generate anti-tumor peptide-dependent CTL effector responses that are not restricted by class la molecules but involve class Ib molecules. Our system models responses against tumors that have down-regulated their class la thereby escaping immune surveillance. It also allows us to study the relationship between hsp and class Ib molecules that are postulated to act as indicators of intracellular stress and malignancy.
Four specific aims are proposed:
Aim 1. What are the functional characteristics of the anti-tumor CCU-CTLs? Aim 2. Do hsp70 and gp96 generate similar anti-tumor CCU-CTL effectors? Aim 3. How important is the hsp-generated CCU-CTL responses in tumor immunity in vivo? Aim 4. Do CCU-CTLs interact with class Ib molecules?
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