Panjwani, Naveed Nooruddin; (1999) The involvement of heat shock protein molecular chaperones in MHC class II antigen processing and presentation. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

MHC class II molecules acquire proteolytically generated antigenic peptides intracellularly and display them on the surface of antigen presenting cells to CD4+ T-cells. Indirect evidence exists that heat shock protein (HSP) molecular chaperones, conserved proteins with indiscriminate peptide binding and ATPase-coupled peptide release properties, participate in the processing and/or presentation of MHC class II associated peptides. HSPs may act as peptide stabilisers, translocators or factors for the rapid loading of peptide onto empty MHC class II αβ dimers. Here, the functional involvement of HSP molecular chaperones in antigen processing and the nature of antigen-chaperone interaction is investigated. Overexpression of both hsp60 and hsc73 resulted in enhancement of antigen processing and presentation capacity without affecting cell surface MHC class II expression. Subcellular localisation of hsp60 is outside its physiological mitochondrial site only in hsp60 overexpressing cells, whereas hsc73 co-compartmentalises with MHC class II molecules in untransfected and hsc73 overexpressing cells. Both chaperones were shown to interact with antigen internalised by APCs in vivo in an ATP sensitive manner. The interaction of hsc73 with antigen is disrupted by the hsc73 binding reagent 15, deoxyspergualin, whereas hsp60/antigen interaction is unaffected. Functionally, this reagent disrupts the ability of both hsc73 overexpressing cells and untransfected 97.2 cells to process and present antigen. Hsp60 overexpression was also shown to result in the rescue of an endogenous epitope from an exclusively intracellular antigen, and a mutant version of hsp60 predicted to lack ATPase function was shown to have a marginal impact on APC function when expressed as a transgene compared to the ATPase competent wild type hsp60. These results indicate that HSP molecular chaperones participate in antigen processing function, with hsc73 possessing characteristics which make it the most likely physiological candidate for such functions.

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