apyrase and Hepatitis

γδ T cells have been shown to have immunoregulatory functions in several experimental autoimmune models. A mutation of the Foxp3 gene leads to the absence of regulatory T cells (Tregs) and a fatal systemic autoimmune disease in scurfy mice. Transfer of scurfy lymphocytes to RAG deficient (RAG(-/-)) recipients reproduces the inflammatory phenotype of the scurfy donor, including hepatitis and pneumonitis. In this study, we show that TCRα(-/-) recipients, which lack αβ T cells but have γδ T cells and B cells, are significantly protected from the hepatitis and pneumonitis, but not the dermatitis, induced by adoptive transfer of scurfy lymphocytes. Cotransfer of γδ T cells, but not B cells, prevented hepatitis and pneumonitis in RAG(-/-) recipients of scurfy lymphocytes. γδ T cells in the TCRα(-/-) recipients of scurfy cells markedly expanded and expressed a highly activated (CD62L(lo)CD44(hi)) phenotype. The activated γδ T cells expressed high levels of CD39 and NKG2D on their cell surface. A high frequency of scurfy T cells in TCRα(-/-) recipients produced IL-10, suggesting that γδ T cells may enhance suppressor cytokine production from scurfy T cells in TCRα(-/-) recipients. This study indicates that γδ T cells may contribute to the maintenance of immunological homeostasis by suppressing autoreactive T cells in liver and lung.

Topics: Adoptive Transfer; Animals; Antigens, CD; Apyrase; Autoimmune Diseases; Autoimmunity; Dermatitis; Forkhead Transcription Factors; Hepatitis; Homeostasis; Interleukin-10; Liver; Lung; Lymphocyte Activation; Mice, Inbred C57BL; NK Cell Lectin-Like Receptor Subfamily K; Pneumonia; Receptors, Antigen, T-Cell, alpha-beta; Receptors, Antigen, T-Cell, gamma-delta; T-Lymphocytes, Regulatory

Adenosine triphosphate (ATP), an essential metabolic energy source, is released following cell apoptosis or necrosis. It acts as a damage-associated molecule pattern to stimulate innate immune cells. The ectonucleotidase CD39 regulates immune activation by hydrolysis of extracellular ATP. We have shown previously that CD39 expression by donor livers helps protect syngeneic grafts with extended (24h) cold preservation time from ischemia reperfusion injury. Given its immune regulatory properties, we hypothesized that CD39 expression in donor livers might modulate transplant tolerance that occurs following mouse allogeneic liver transplantation (LTx). Livers from C57BL/6 (B6) wild-type (WT) or CD39 KO mice were transplanted into normal C3H recipients with minimal (approximately 1h) cold ischemia. Serum alanine aminotransferase levels at day 4 post-LTx were significantly higher in animals given CD39KO compared with WT livers. Moreover, IFN-γ production by liver-infiltrating CD8(+) T cells at day 4 was significantly higher in CD39KO than in WT grafts. Furthermore, splenic T cells from CD39KO liver recipients exhibited greater proliferative responses to donor alloantigens than those from mice given WT grafts. By contrast, there was a concomitant significant reduction in the frequency of regulatory T cells (Treg) in CD39KO than in WT livers. Whereas WT liver allografts survived >100 days, no CD39KO grafts survived beyond 40 days (median survival time [MST]: WT: >100 days vs CD39KO: 8 days; p<0.01). In addition, soluble CD39 administration significantly prolonged CD39KO liver allograft survival (MST: 27.5 days). These novel data suggest that CD39 expression in liver allografts modulates tissue injury, inflammation, anti-donor effector T cell responses and Treg infiltration and can suppress transplant rejection.

Topics: Allografts; Animals; Antigens, CD; Apyrase; Graft Rejection; Graft Survival; Hepatitis; Liver Transplantation; Male; Mice; Mice, Knockout