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Self-Reactivity in a Lymphopenic Mouse: A Model of Acute Graft-versus-Host Disease.

Transfer of naive antigen-specific T cells into self-antigen expressing transgenic mice leads to the development of hyporesponsiveness and deletion of the self-reactive T cells. This form of functional tolerance is characterized by decreased recall responses both in vivo and in vitro. Although the development of tolerance has been studied extensively, few studies have analyzed the factors that determine the breakdown of tolerance and how host cell populations influence the process. Using transgenic mice that express a secreted form of ovalbumin (sOVA Tg) in the serum either on a wildtype (WT) or a T-cell deficient (TCRa−/−), or B- and T-cell deficient (Rag−/−) background, we investigate tolerance development of OVA-specific DO11.10 CD4+ T cells that have been transferred into these mice. We report kinetics, phenotypes and cytokine production of the antigen-specific T cells after transfer. We further describe the histological, immunohistochemical and clinical picture and the effects of cytokine blockade by administration of antibodies. Naive OVA-specific T cells that encounter OVA as a self-antigen in lymphocyte-sufficient recipients undergo some expansion, followed by a contraction phase, and become functionally hyporesponsive to the antigen. In contrast, adoptive transfer of DO11 cells into Rag-deficient sOVA Tg animals results in rapid development of wasting and death, phenotypically and histologically resembling cytokine release syndrome or acute GvHD. Histologic examination reveals inflammatory infiltrates predominantly in the skin and gut. Under these circumstances the transferred DO11 cells undergo massive expansion and produce abundant amounts of IL-2 and IFN-g. In contrast, transfer into TCRa-deficient sOVA Tg animals, in which B cells are present, leads to similar T cell expansion but substantially reduced IFN-g production and no death. Our data suggest that T cell tolerance in vivo is critically dependent on an intact, lymphocyte-sufficient host. In the absence of endogenous lymphocytes, T cells specific for a systemic self-antigen are activated and cause lethal immune reactions.