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TCR-Mediated Involvement of CD4⁺ Transgenic T Cells in Spontaneous Inflammatory Bowel Disease in Lymphopenic Mice¹

Woon-Puay Koh^*, Elsie Chan^*, Kate Scott^*, Geoffrey McCaughan^*, Malcolm France and Barbara Fazekas de St. Groth^2,*

^* Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia; and Department of Veterinary Pathology, University of Sydney, Sydney, Australia

Spontaneous colitis resembling ulcerative colitis developed in 3 of 10 independent TCR transgenic (Tg) mouse lines maintained under specific pathogen-free conditions. All three susceptible lines were CD4 lymphopenic, whereas resistant lines had normal numbers of CD4⁺ T cells. Thus, cytochrome c-specific 5C.C7 TCR Tg mice developed colitis only when crossed onto a SCID- or Rag-1-deficient background. A second line of lymphopenic cytochrome c-specific Tg mice bearing the AND TCR also developed colitis. In both cases, CD4⁺ T cells expressing the Tg-encoded TCR were preferentially activated in inflamed colons compared with lymph nodes or spleens. In contrast, Tg⁺CD4⁺ T cells remained quiescent in both inflamed and unaffected colons in another line of susceptible Tg mice carrying a TCR specific for myelin basic protein, suggesting a fortuitous cross-reactivity of the IE^k-restricted cytochrome c-reactive AND and 5C.C7 TCRs with an Ag present in the gut. The percentage of CD4⁺ T cells expressing only endogenous TCR -chains was increased consistently in inflamed colons in AND as well as 5C.C7 Rag-1^-/- TCR Tg mice, suggesting that polyclonal CD4⁺ T cells were also involved in the pathogenesis of spontaneous colitis. Moreover, our data indicate that some -chain rearrangement was still occurring in TCR Tg mice on a Rag-1^-/- background, since activated CD4⁺ T cells expressing endogenously rearranged -chains paired with the Tg-encoded ß-chain were detected consistently in the colons of such mice.

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