We recently demonstrated that signalling through the cytokine tyrosine kinase receptor flt3 and interleukin-7 receptor α (IL-7Rα ) is indispensable for fetal and adult B cell commitment and development (

Sitnicka et al., J. Exp. Med. 198: 1495, 2003
). We have also shown that flt3 ligand (FL)-deficient mice have reduced levels of the common lymphoid progenitor (CLP) but normal levels of mature T cells (
Sitnicka et al., Immunity, 17:463, 2002
). However, previous studies failed to demonstrate a role of flt3 and its ligand in T lymphopoiesis. Herein, although having normal numbers of thymocytes, FL-deficient mice were shown to have distinct reductions in the earliest double negative (DN) progenitors in the fetal, postnatal and adult thymus. A critical role of flt3 in thymocyte development was most evident in the absence of Interleukin-7 receptor a (IL-7Rα ) signalling. Strikingly, in adult FL−/−IL-7Rα −/− (double deficient) mice thymic cellularity was reduced 400 fold as compared to FL−/− and wild type (WT) controls and 30 fold as compared to IL-7Rα −/− mice. In agreement with previous studies, IL-7Rα −/− thymocytes revealed a partial block at the progression from the DN2 (CD4−CD8−CD44+CD25+) to DN3 (CD4−CD8−CD44−CD25+) stage, while in FL−/−IL-7Rα −/− mice DN1 (CD4−CD8−CD44+CD25−), DN2 and DN3 thymic progenitors were undetectable. The DP CD4+CD8+ thymocytes were reduced more than 1000 fold as compared to IL-7Rα −/− mice and low levels of peripheral T cells remaining in FL−/−IL-7Rα −/− mice had exclusively an activated/memory phenotype. Furthermore, FL−/−IL-7Rα −/− bone marrow cells lacked T cell reconstituting potential after transplantation into lethally irradiated recipients. Taken together these data demonstrate indispensable and complementary roles of flt3 and IL-7Rα in T lymphopoiesis.

Topics:
fetus, flt3 gene, lymphopoiesis, ms-like tyrosine kinase 3, antigens, cd25, cd44 antigens, homing-associated cell adhesion molecule, interleukin 7 receptor, cytokine, flt3 ligand

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2005, The American Society of Hematology
2005
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