Critical and Complementary Role of FLT3 and Interleukin 7-Receptor Alpha Signaling in T Lymphocyte Development.

We recently demonstrated that signaling through the cytokine tyrosine kinase receptor flt3 and interleukin-7 receptor a (IL-7Ra) is indispensable for fetal and adult B cell commitment and development (Sitnicka et al., J. Exp. Med. 198: 1495, 2003). These receptors are also implicated to be important in regulation of T cell development, but their potential interdependence remains unexplored. We recently showed that flt3 ligand (FL)-deficient mice have reduced levels of early thymic progenitors as well as the common lymphoid progenitor (CLP) (Sitnicka et al., Immunity, 17:463, 2002). In the present study we investigated T cell development in mice deficient in FL and IL-7Ra expression. Strikingly, when compared to FL^−/− and IL-7Ra^−/− mice, FL^−/−xIL-7Ra^−/− (double deficient) mice (8-10 week old) lack visible lymph nodes and Peyer’s Patches. Thymic cellularity was dramatically reduced to only 0.3% of FL^−/− and wild type (WT) controls and to only 4% of IL-7Ra^−/− mice. In agreement with previous studies, IL-7Ra^−/− 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^−/−xIL-7Ra^−/− mice DN1 (CD4⁻CD8⁻CD44⁺CD25⁻), DN2 and DN3 thymic progenitors were undetectable. Thus, severe reductions in early thymocyte development in FL^−/−xIL-7Ra^−/− mice support a similar role for cross talk between these two signaling pathways in T cell development as recently demonstrated for B cell genesis.