Roles of hematopoietin and cytokine tyrosine kinase receptors in early lymphopoiesis

Sammanfattning: 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.