title: Functionally divergent T lymphocyte responses induced by modification of a self-peptide from a tumor-associated antigen.
abstract: The N- and C-terminal flanking domains of the invariant chain peptide, CLIP, have remarkable immunological properties. Addition of these flanking domains to a foreign peptide antigen increases its immunologic potency. The present studies evaluated whether altering a peptide ligand from the tumor-associated antigen c-neu with the flanking domains of CLIP could modify the systemic immune response. The results indicate that the immunogenicity of an MHC class II restricted peptide (NEU) derived from c-neu was significantly altered by addition of the flanking domains from CLIP. Interestingly, selective modification of the peptide with either the N- or the C-terminal flanking domains resulted in functionally divergent systemic immune responses. Immunization of normal F344 rats with the NEU peptide modified with the N-terminal domain of CLIP (N-NEU) resulted in an immune response primarily consisting of type 1 (IL-2, IFNgamma) cytokine producing T cells. On the other hand, type 2 (IL-4) cytokine responses were largely predominant following immunization with the self-peptide modified with the C-terminal flanking domain (NEU-C). The functionally divergent responses elicited by the modified self-peptides were accompanied by significant changes in the expression of the CD28/CTLA4/B7 family of co-stimulatory molecules. Immunization with the N-NEU peptide led to enhanced expression of CD28 in the antigen-specific, CD4+ T cell compartment while expression of B7.1 was dramatically reduced in antigen-specific CD8+ T cells. Comparatively, expression of CTLA4 was down-regulated in the antigen-specific CD4+ T cell compartment following immunization with NEU-C peptide. The N-NEU peptide also had a direct effect on dendritic cells leading to the up-regulation of B7.1 expression. Taken together, functionally divergent systemic immune responses can be elicited by strategically altering a self-peptide ligand with the N- and C-terminal flanking domains of CLIP. Moreover, changes in expression of co-stimulatory molecules that are required for T cell activation and T cell-T cell communication may account for the polarization of the immune response elicited by the chimeric peptides.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 1650 Orleans Street, Room 489, Baltimore, MD 21231, USA. adhess@jhmi.edu
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Thoburn
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miura
authors.forename: Emilie C
authors.initials: EC
authors.lastname: Bright
mesh_terms: D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D010446:Peptide Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; C045084:invariant chain