ab1904

Immunization with TCR Vb10 peptide reduces the frequency of type-II collagen-specific Th1 type T cells in BUB/BnJ (H-2q) mice

D.D. Anthony¹, P.S. Heeger^1,2, T.M. Haqqi¹

¹Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, and ²The Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland OH, USA.

ABSTRACT
Objective
Collagen induced arthritis (CIA) in mice is mediated by synergistic T cell and humoral immune responses specific for type II collagen (CII). We have previously shown that in arthritic joints of BUB mice (TCR Vb^a, H-2^q) the TCR repertoire is enriched for Vb10 expressing T cells, and that immunization with a Vb10 peptide (Vb10p) prevents the phenotypic expression of disease. The objective of the present study was to understand how immunization with a synthetic TCR Vb peptide affected the development of the pathogenic CII-specific immune response in BUB mice.

Methods
Arthritic and protected animals were tested for Vb10p- and CII-specific cytokine production by a highly specific and sensitive ELISA spot assay, and for CII-specific antibody production by standard ELISA. In adoptive transfer experiments, Vb10p-specific LN cells (INF-g producing) were injected into naive mice prior to immunization with type-II collagen/CFA.

Results
Immune cells from arthritic animals produced IFN-g and IL-2, without IL-4 and IL-5 in response to CII and an immunodominant epitope, A2, derived from CII. Serum from these mice contained anti-CII antibodies of both IgG1 and IgG2a subtypes. Our results show for the first time that immunization with Vb10p resulted in Vb10p-specific IFN-g and IL-2 production that was restricted to the CD4+ T cell subset. Emergence of this Vb10p-specific immune response was associated with a dramatic decrease in the frequency of CII and A2-specific, cytokine producing T cells in arthritis protected mice. Protective immunity was cell mediated and could be adoptively transferred. In contrast, the protective immunization had only a marginal effect on the anti-CII antibody response indicating that the CII specific humoral immune response was not significantly affected.

Conclusion
Immunization with TCR Vb10p leads to expansion of a population of Vb10p- specific CD4+ T cells. This anti-TCR Vb10p specific type 1 cytokine producing immune response was protective in adoptive transfer studies and appears to inhibit the expansion of the pathogenic anti-CII cellular immunity. Additionally, the anti-TCR Vb10p-specific cellular immune response was mediated by CD4+ T cells and these T cells did not produce IL-4 or IL-5. Thus, our results suggest that protection against CIA in mice immunized with synthetic TCR Vb10p was achieved by a specific down-regulation of the CII-specific Th1 type cellular immune response and not via immune deviation.

Key words
Arthritis, animal models, TCR, vaccination, T cell.

This work was supported by NIH grants AR-44902, AR-20618 (NEOMAC), Rheumatology-Orthopedics Training Grant AR-07505 (for DDA) and by a Biomedical Science Grant from the Arthritis Foundation.

Please address correspondence and reprint requests to: Dr. Tariq M. Haqqi, Case Western Reserve University, Department of Medicine, Division of Rheumatic Diseases, 2109 Adelbert Road, BRB-1023, Cleveland, Ohio 44106-4946, USA.
E mail: txh5@po.cwru.edu