Functionally divergent T lymphocyte responses induced by modification of a self-peptide from a tumor-associated antigen

• Published in: Clinical immunology (Orlando, Fla.) Fla.), 2005-03, Vol.114 (3), p.307-319
• Main Authors: Hess, Allan D., Thoburn, Christopher J., Miura, Yuji, Bright, Emilie C.
• Format: Article
• Language: English
• Subjects: Animals; Antigens, Differentiation, B-Lymphocyte - immunology; Antigens, Neoplasm - immunology; Biological and medical sciences; C-neu; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; CLIP; Co-stimulatory receptors; Cytokine polarization; Cytokines - metabolism; Female; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Histocompatibility Antigens Class II - immunology; Immunopathology; Invariant chain peptide; Medical sciences; MHC class II; Peptide Fragments - immunology; Peptide Fragments - pharmacology; Peptide modification; Rats; Receptor, ErbB-2 - chemistry; Receptor, ErbB-2 - immunology; Self-antigen; Spleen - cytology; Spleen - drug effects; Spleen - immunology; T cell repertoire diversity; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tumor-associated self-antigen
• ISSN: 1521-6616; 1521-7035
• DOI: 10.1016/j.clim.2004.11.004

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, IFNγ) 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.