Cytokine Modulation of Thymopoiesis

Abstract

The thymus is an organ derived from embryonic endoderm and mesoderm differentiation. It is located above the heart and is made up of two compartments, the thymic epithelial space and the perivascular space. The thymic epithelial space consists of the cortex and the medulla, which is where T cell development, maturation and induction of self tolerance occur in a process known as thymopoiesis. The thymus is susceptible to chronic and acute stressors that result in thymic involution. A consequence of thymic involution is reduced thymopoiesis, which affects the generation of a diverse T cell repertoire and establishment of central T cell tolerance. Many thymosuppressive and thymostimulatory cytokines are involved in thymopoiesis and thymic involution. Keratinocyte growth factor and IL-7 are two cytokines that function in driving early thymic progenitor proliferation and T cell development, respectively. We hypothesized that IL-7 and Keratinocyte growth factor, delivered via recombinant adenovirus, can improve thymopoiesis and T cell reconstitution in mice in an endotoxin model of acute thymic atrophy. Analysis of thymus weight, cellularity, phenotype and TCR gene rearrangement showed moderate increases in thymic function with delivery of IL-7 or Keratinocyte growth factor versus control. Taken together, these data suggested that IL-7 and Keratinocyte growth factor, delivered via recombinant adenoviruses, have thymostimulatory effects on the thymus in normal thymus or settings of acute thymic atrophy and maybe beneficial for future development as therapeutics.