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Fully Functional HLA B27-Restricted CD4⁺ as well as CD8⁺ T Cell Responses in TCR Transgenic Mice

Matthew Roddis^*, Robert W. Carter^*, Mei-Yi Sun, Thomas Weissensteiner^*, Andrew J. McMichael, Paul Bowness and Helen C. Bodmer^1,*

^* Edward Jenner Institute for Vaccine Research, Compton, Newbury, United Kingdom; and Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

The strong association of HLA B27 with spondyloarthropathies contrasts strikingly with most autoimmune diseases, which are HLA class II associated and thought to be mediated by CD4⁺ T lymphocytes. By introducing a human-derived HLA B27-restricted TCR into HLA B27 transgenic mice, we have obtained a functional TCR transgenic model, GRb, dependent on HLA B27 for response. Surprisingly, HLA B27 supported CD4⁺ as well as CD8⁺ T cell responses in vivo and in vitro. Further, HLA B27-restriced CD4⁺ T cells were capable of differentiation into a range of Th1 and Th2 T cell subsets with normal patterns of cytokine expression. The transgenic T cells were also able to enhance clearance of recombinant vaccinia virus containing influenza nucleoprotein in vivo. This is the first description of a human HLA class I-restricted TCR transgenic line. The existence of CD4⁺ MHC class I-restricted T cells has significant implications for immune regulation in autoimmunity and, in particular, in HLA B27-associated arthritis. We believe that this model provides a novel system for the study of unusual T cell behavior in vivo.

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