A20 deletion in T cells modulates acute graft-versus-host disease in mice

作者：Fischer Julius C; Otten Vera; Steiger Katja; Schmickl Martina; Slotta Huspenina Julia; Beyaert Rudi; van Loo Geert; Peschel Christian; Poeck Hendrik^*; Haas Tobias^*; Spoerl Silvia^*

来源：European Journal of Immunology, 2017, 47(11): 1982-1988.

DOI：10.1002/eji.201646911

• A20
• Allogeneic hematopoietic stem cell transplantation
• Graft-versus-host disease
• Inflammatory response
• T cells

The NF-kappa B regulator A20 limits inflammation by providing negative feedback in myeloid cells and B cells. Functional lack of A20 has been linked to several inflammatory and autoimmune diseases. To define how A20 affects the functionality of T effector cells in a highly inflammatory environment, we performed conventional allogeneic hematopoietic stem cell transplantation (allo-HSCT) with A20-deficient CD4(+) and CD8(+) donor T cells in mice. Severity and mortality of graft-versus-host disease (GVHD) after allo-HSCT was drastically reduced in recipients transplanted with conventional doses of A20-deficient T cells. Consistently, we found that the A20-deficient donor T-cell compartment was strongly diminished at various timepoints after allo-HSCT. However, proportionally more A20-deficient donor T cells produced IFN-gamma and systemic inflammationwas elevated early after allo-HSCT. Consequently, increasing the dose of transplanted A20-deficient T cells reversed the original phenotype and resulted in enhanced GVHD mortality compared to recipients that received A20(+/+) T cells. Still, A20-deficient T cells, activated either through T cell receptor-dependent or -independent mechanisms, were less viable than control A20(+/+) T cells, highlighting that A20 balances both, T-cell activation and survival. Thus, our findings suggest that targeting A20 in T cells may allow to modulate T-cell-mediated inflammatory diseases like GVHD.

• 出版日期2017-11