The functional role of class II-associated invariant chain peptide (CLIP) in its ability to variably modulate immune responses

Curing the process of class II MHC assembly and cell surface expression, th e class Ii-associated invariant chain peptide (CLIP) is removed from the pe ptide-binding groove of MHC, a task mediated by H-2M, This allows binding a nd presentation of peptide epitopes, We have previously shown that exogenou sly added CLIP interferes with this process and down-regulates the cell sur face expression of class II molecules. In this study, we explored the effec t of exogenously added CLIP on antigen-specific immune responses. In vivo s tudies with CLIP and various peptide and protein antigens with different af finities for I-A(d) molecules demonstrated that CLIP variably affects the T cell-mediated immune responses. Immunization with CLIP along with the anti gen induced a shift from a T(h)1- to T(h)2-like response as determined by t he cytokine profile and antibody isotype, These results suggest that the pr esence of exogenous CLIP can significantly influence the presentation of an tigen by class II MHC molecules to CD4 T cells and thereby modulate immune responses. Exogenously added CLIP rapidly localized into the subcellular co mpartment of antigen-presenting cells where MHC class II molecules are pres ent. We suggest that exogenous CLIP reduces the loading of peptides on the class II molecules, thus down-regulating MHC-peptide complexes on the cell surface. Alternatively, CLIP may bind to cell surface class II molecules an d this complex is rapidly internalized resulting in reduced cell surface MH C class II expression. The reduced level of MHC-peptide complexes favors th e activation of T(h)2 cells over T(h)1 cells. These results have implicatio ns in the regulation of immune responses, particularly the prevention of ce rtain autoimmune diseases where T(h)1-type responses are pathogenic and T(h )2-type responses are protective.