FLVCR, a heme export protein, is required for T cell development beyond the CD4+CD8+ double-positive stage (64.18)

Abstract

Abstract Heme is essential for every mammalian cell; however, free heme can induce free radical formation and cellular damage and cells must carefully regulate heme levels. The feline leukemia virus subgroup C receptor (FLVCR) exports heme from cells. Deletion of Flvcr caused progressive anemia in neonatal and adult mice (Science 319:825-8, 2008). We developed a transplant model in which developing lymphocytes lacked FLVCR while erythroid cells expressed FLVCR, preventing anemia, and found that CD4 and CD8 peripheral T cells were severely decreased while B cell numbers were only mildly affected. We analyzed thymic development and found that although there were similar numbers of CD4-CD8- double-negative thymocytes (DN) and CD4+CD8+ double-positive thymocytes (DP), there was a dramatic decrease in the number of CD4+ and CD8+ single positive thymocytes (SP) in FLVCR KO-transplanted mice. Because sensitive quantification of intracellular free heme is challenging, we measured the relative expression of a heme-inducible gene, heme oxygenase-1 (hmox-1) and found higher hmox-1 expression in FLVCR KO thymocytes compared to controls, suggesting that Flvcr deletion leads to higher intracellular free heme in developing T cells. While heme is required for erythroid function, there is no known specific role for heme in T cell development. Studies are underway to determine whether direct heme toxicity arrests T cell development, or whether excess heme alters T cell developmental gene expression.