Ia molecules are polymorphic glycoproteins which regulate the major histocompatibility complex (MHC)-restricted recognition of the cooperating cells that bear them with a class of T cells (Class II restricted) that includes the bulk of the T?H? (helper cell) population. On the surface of the antigen-presenting cell (APC), Ia molecules are recognized together with processed exogenous antigen, and thereby trigger the T cell to a differentiative response resulting in """"""""activation,"""""""" i.e., capability to deliver help in an antigen-restricted (Ir-gene controlled) fashion. On the surface of the cell receiving help, Ia molecules promote recognition by the antigen-activated T?H? cell, resulting in delivery of a signal to differentiate. The differential capacities of Ia molecules to promote response to a particular antigenic determinant (Ir gene effect) is dependent on variation in Ia primary structure (amino acid sequence). In addition, there is evidence that secondary structural features (post-translational modifications) of Ia molecules, which vary on functionally different cell types, influence the recognition of Ia by T cells. This work involves: (1) description of secondary structural features of Ia, such as N-linked oligosaccharide, in functionally different cell populations; (2) correlation of such structural features with functions such as antigen-specific T-cell binding and proliferation; and (3) intentional modification of the secondary structure to generate changes in function. We will also be examining the role of a newly discovered chondroitin sulfate proteoglycan (CSPG) specifically associated with Ia in modifying the interaction of Ia with T cells. Methods to be employed are T cell binding and proliferation assays, serial lectin affinity chromatography, exoglycosidase sequencing, and in situ manipulations of la expression or structure by pharmacological, enzymatic, or other approaches. (AG)
