Intraepithelial lymphocytes (IEL) of the small murine bowel represent a unique population of mostly CD8 + T lymphocytes that reside within the epithelial cell layer of the intestinal mucosa. The close interaction with epithelial cells appears to be crucial for IEL survival since isolation and ex vivo culture induces massive apoptosis in this lymphocyte population. Here, we provide evidence that this form of IEL cell death may be mediated at least in part by endogenously produced glucocorticoids since adrenalectomy or treatment of mice with a glucocorticoid receptor antagonist significantly enhanced ex vivo survival of IEL. We further demonstrate that ex vivo activation of IEL induces upregulation of antiapoptotic gene products, compensates for the lack of survival cytokines and rescues from apoptotic cell death. Thus, similar to thymocytes and T cell hybridomas, IEL survival may be regulated by the antagonistic action of TCR activation and glucocorticoids. Cell Death and Differentiation (2001) 8, 706 ± 714.

Fas (CD95/APO-1) ligand (FasL)-mediated cytotoxicity has been implicated in tissue destruction in a variety of diseases, including acute graft-vs-host disease (GVHD). In this study, we have analyzed FasL expression and regulation during the course of experimental murine acute GVHD. Although activation-induced FasL-mediated cytotoxicity in control T cells was sensitive to the immunosuppressant cyclosporin A, we observed that functional FasL expression of GVHD T cells became increasingly cyclosporin A unresponsive. This was found to be the result of a massive in vivo accumulation and intracellular storage of FasL protein and its release in a transcription- and protein synthesis-independent manner. Immunohistochemistry analysis of FasL expression in situ revealed accumulation of FasL-expressing cells in the spleen, the liver, and small intestine, with a typical cytoplasmic and granular expression pattern. Thus, we conclude that the release of preformed FasL by infiltrating donor T cells may contribute to recipient tissue damage during the pathogenesis of acute GVHD.

It is still elusive why certain self proteins induce an autoimmune response. One immunological hypothesis is that only modified or altered self‐proteins may become a target. Thus, we asked whether such alterations may actually be genetic polymorphisms that can be revealed by analyzing sequence variability in the known human autoantigens. Indeed, we found autoantigens to contain significantly more single nucleotide polymorphisms (SNP) than other human genes do. Our finding may offer an explanation for autoimmune responses through allogeneic exposure. Besides other contributing factors in autoimmunity, SNP may represent an essential prerequisite for the primary induction of an autoimmune response.See accompanying Commentary: http://dx.doi.org/10.1002/eji.200425888

Acute graft-versus-host disease (GvHD) is a serious complication after allogeneic bone marrow transplantation. Donor-derived T cells infiltrate recipient target organs and cause severe tissue damage, often leading to death of the affected patient. Tissue destruction is a direct result of donor CD8+ T cell activation and cell-mediated cytotoxicity. IL-18 is a novel pro-inflammatory cytokine with potent T(h)1 immune response-promoting and cytotoxic T lymphocyte (CTL)-inducing activity. IL-18 is strongly induced in experimental mouse models and human patients with acute GvHD. However, the precise role of IL-18 in the development of acute GvHD is still unknown. In this study, we have used IL-18-binding protein, a soluble IL-18 decoy receptor, to specifically neutralize IL-18 in vivo and in vitro. Our results demonstrate that IL-18 is induced during GvHD. However, its effect in the induction of GvHD appears to be redundant, since neutralization of IL-18 does not alter any disease parameter analyzed. Our study further shows that IFN-gamma production and CTL induction upon activation by T cell mitogens or by alloantigen does not involve IL-18-mediated amplification, in contrast to lipopolysaccharide-induced IFN-gamma production. We conclude that IL-18 expression correlates with the course of GvHD; however, its effect is dispensable for IFN-gamma and CTL induction for the initiation phase of this disease, most likely due to direct, IL-18-independent, CTL activation.