title: Tuning T cell activation threshold and effector function with cross-reactive peptide ligands.
abstract: We have generated a panel of cross-reactive T cells by immunizing SJL mice (I-A(s)) with Q144 peptide, an analog of an autoantigenic peptide (W144) of myelin proteolipid protein (PLP) 139-151 (HSLGKWLGHPDKF) in which W was replaced by Q at position 144. Following immunization with Q144, T cells were expanded in vitro with W144, which is a cross-reactive, suboptimal ligand, for Q144-specific T cells. The T cell clones responded to both ligands and grew normally on the peptide W144, but were hyperstimulated when activated by Q144 in vitro. This hyperstimulation results in a heteroclitic proliferative response with secretion of additional cytokines not induced by W144. Thus expansion of T cells by a suboptimal cross-reactive ligand effectively lowers the activation threshold so that the immunizing antigen becomes a hyperstimulating ligand for the clones. Surprisingly, when the T cell clones are grown on the hyperstimulating ligand Q144, some adapt by increasing their activation threshold. This desensitization results in a loss of response to a number of cross-reactive ligands and the appearance of a more specific T cell response. Long-term culture with the hyperstimulating ligand is sometimes associated with down-regulation of CD4 expression. These results provide an explanation for the common finding of T cell heteroclicity, and suggest that although the specificity and hierarchy of the response of T cells to peptides is determined by the TCR, activation threshold and effector functions are modified by exposure to cross-reactive ligands. This observation has implications for the development and regulation of autoimmune disease.
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Nicholson
authors.forename: A C
authors.initials: AC
authors.lastname: Anderson
authors.forename: V K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D015704:CD4 Antigens / Q000378:metabolism; D002999:Clone Cells; D003429:Cross Reactions / Q000276:immunology; D005260:Female; D005434:Flow Cytometry; D008024:Ligands; D008213:Lymphocyte Activation; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D010455:Peptides / Q000276:immunology* / Q000494:pharmacology; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D015704:CD4 Antigens; D008024:Ligands; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; C435023:myelin proteolipid protein (139-151)