Inhibition of gamma delta T cell development and early thymocyte maturation in IL-7 -/- mice.

Abstract

While early thymic T cell precursor populations and their maturational sequence have been recently identified, the signals driving differentiation are unknown. While cytokines may play an integral role in T cell development, various mouse models rendered genetically deficient for specific cytokines do not display abnormalities in T cell development. Recently, we have generated IL-7 -/- mice and reported that IL-7 plays a unique and nonredundant role in lymphopoiesis. These mice displayed a 10- to 20-fold reduction in the total number of T and B cells. Here, we show that IL-7 -/- mice display a sharp reduction in both the frequency and absolute number of adult thymic gamma delta T cells while retaining normal frequencies of alpha beta T cells. This defect in gamma delta T cell production extends to peripheral organs as IL-7 -/- mice are essentially devoid of splenic and intestinal intraepithelial gamma delta T cells. This aberrant phenotype was traced back to impaired fetal gamma delta T cell maturation. In the absence of IL-7, differentiation of immature V gamma 3 low-CD24+ fetal T cells to mature V gamma 3 high CD24- cells is inhibited. In contrast, NK cell maturation appears to be only mildly affected in the absence of IL-7. To further clarify the role of IL-7 in thymic development, detailed analysis of CD3-4-8- thymic precursors was performed. A partial inhibition in the differentiation of CD44+25+ pro-T cells into CD44-25+ pre-T cells was observed. Unexpectedly, the lack of IL-7 resulted in decreased expression of CD117 (c-kit) on both CD4 low and pro-T cells, suggesting that IL-7 may influence the expression of other cytokine receptors involved in early hemopoietic development. Together, these data clarify the developmental abnormalities during T cell development due to the absence of IL-7.