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TNF-TNFR2 Interactions Are Critical for the Development of Intestinal Graft-Versus-Host Disease in MHC Class II-Disparate (C57BL/6JC57BL/6J x bm12)F₁ Mice¹

Geri R. Brown^2,*,, Ed Lee^, and Dwain L. Thiele^*

^* Division of Digestive and Liver Diseases, Departments of Internal Medicine and Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and Dallas Veterans Affairs Medical Center, Dallas, TX 75216

TNF-TNFR2 interactions promote MHC class II-stimulated alloresponses while TNF-TNFR1 interactions promote MHC class I-stimulated alloresponses. The present studies were designed to evaluate whether TNF-TNFR2 interactions were involved in the in vivo generation of CD4⁺ T cell-mediated intestinal graft-versus-host disease (GVHD) in the (C57BL/6J (hereafter called B6)B6 x B6.C-H-2^bm12 (bm12))F₁ GVHD model. Briefly, 5 x 10⁶ splenic CD4⁺ T lymphocytes from B6.TNFR2^-/- or control B6 mice were transferred with 1–2 x 10⁶ T cell-depleted B6 bone marrow cells (BMC) to irradiated MHC class II-disparate (bm12 x B6)F₁ mice. Weight loss, intestinal inflammation, and the surface expression of CD45RB (memory marker) on intestinal and splenic lymphocytes were assessed. IL-2 and IFN- mRNA levels in intestinal lymphocytes were assessed by nuclease protection assays. A significant reduction in weight loss and intestinal inflammation was observed in recipients of the TNFR2^-/-CD4⁺ SpC. Similarly, a significant decrease was noted in T cell numbers and in CD45RB^low (activated/memory) expression on intestinal but not CD4⁺ T cells in recipients of TNFR2^-/-CD4⁺ spleen cells. IL-2 and IFN- mRNA levels were reduced in the intestine in the recipients of TNFR2^-/- splenic CD4⁺ T cells. These results indicate that TNF-TNFR2 interactions are important for the development of intestinal inflammation and activation/differentiation of Th1 cytokine responses by intestinal lymphocytes in MHC class II-disparate GVHD while playing an insignificant role in donor T cell activation in the spleen.

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