Roles of hematopoietin and cytokine tyrosine kinase receptors in early lymphopoiesis

Cytokines have been shown to have important roles in lymphopoiesis. However, many questions remain unresolved. Among other, while the action of interleukin (IL)-7 in alpha beta T cell development in mouse seems to be largely mediated through permissive survival signaling, the possible permissive role of IL-7 in early B cell development is disputed. Furthermore, FMS-like tyrosine kinase-3 ligand (FLT3L) has been shown to be important in IL-7 receptor alpha chain (IL-7R)-independent B and T lymphopoiesis but little is known of its mode(s) of action. Moreover, although little direct evidence exists, thymic stromal lymphopoietin (TSLP) has been suggested to be a key regulator of fetal and adult IL-7-independent lymphopoiesis. Herein, I explored, through studies of single and double cytokine receptor and ligand knockout mice, the relative roles of TSLP, IL-7 and FLT3L as well as a potential permissive role for FLT3L and IL-7 in early B and T cell development.
We demonstrate that rather than TSLP, IL-7 and FLT3L are critical for B and T cell generation in mice. Furthermore, we demonstrate that ectopic expression of B cell lymphoma 2 (BCL2) is sufficient not only to correct the T cell phenotype of FLT3L deficient mice but can also rescue the virtually complete loss of all discernable stages of early T lymphopoiesis in double FLT3L and IL-7R deficient mice. Furthermore, the same overexpression studies suggest that FLT3 and IL-7R are capable of also mediating survival signaling in early B cell development. These findings implicate a permissive role of cytokine receptors of the hematopoietin as well as the tyrosine kinase families in early B and T lymphopoiesis.