Cytokine imbalance and autoantibody production in T cell receptor-α mutant mice with inflammatory bowel disease

Abstract

Spontaneous inflammatory bowel disease (IBD) resembling human ulcerative colitis develops in mice mutant for the T cell receptor α gene (TCR-α(-/- ). TCR-α(-/-) mice lack TCR-α/β+ cells but contain TCR-γ/δ+ cells and a small population of a unique Cd4+, TCR-α+/β(+ flow) cells. Since all the immunoglobulin (Ig) classes are present in these mice, help to B cells must be provided by cells other than TCR-α/β+ cells. In the present study, we found serum levels of IgG1 and IgG2 to be markedly increased in TCR-α(- /-) mice with IBD as compared to TCR-α(-/-) mice without IBD or TCR-α(+/-) controls. An increase in IgG1-, IgG2a- and IgA- but not IgM-secreting mesenteric lymph node (MLN) B cells was detected in TCR-α(-/-) mutant mice. There was also a marked increase in MLN B cells secreting autoantibody (IgG) to tropomyosin, a cytoskeletal protein. Examination of the hyperplastic MLN showed a marked increase in the number of B, TCR-δ+, and CD4+ TCR-α- /β+ cells, similar to the cell population observed at the site of colonic inflammation. Analysis of spontaneous cytokine production by MLN cells using an enzyme-linked immunospot assay, immunohistochemistry, and reverse transcription-polymerase chain reaction showed a decrease of interleukin 2 (IL-2) but a marked increase of IL-4 and interferon γ (IFN-γ) production in TCR-α(-/-) mice with IBD as compared to TCR-α(-/-) mice without IBD and TCR-α(-/-) control mice. Both TCR-α-/β+ and TCR-δ+ cells were found to be capable of producing IL-4; IFN-γ was produced mostly by non-T cells, many of which were shown to be CD3 NK 1.1+ cells. We propose that the cytokine imbalance present in these mice results in expansion of B cells, production and switching of autoantibodies to IgG2 subclass, and development of IBD. It is possible that the unusual CD4+ TCR-α-/β+ population and expanded TCR- γ/δ+ population present in TCR-α(-/-) mice plays a central role in this abnormal immune response.