The Survival and Differentiation of Pro-B and Pre-B Cells in the Bone Marrow Is Dependent on IL-7R alpha Tyr(449)

作者：Patton Daniel T; Plumb Adam W; Abraham Ninan^*

来源：The Journal of Immunology, 2014, 193(7): 3446-3455.

DOI：10.4049/jimmunol.1302925

IL-7 is critical for murine T and B cell development and survival and plays a significant role in lymphoblastic leukemia in both humans and mice. We evaluated the role of the IL-7R alpha Tyr(449) cytoplasmic SH2-binding motif in IL-7-mediated B cell development using a knock-in mouse with a Tyr to Phe mutation (IL-7R alpha(449F/449F) mouse). IL-7R alpha(449F/449F) and IL-7R alpha(-/-) mice showed no defect in the number of pre-pro-B cells, although IL-7R alpha(449F/449F) mice had decreased Ebf1 in pre-pro-B cells and impairment in B cell-committed CLPs. We identified that IL-7R alpha(449F/449F) was critical for both pro-B and pre-B stages of development in the bone marrow. IL-7R alpha(449F/449F) and IL-7R alpha(-/-) mice had comparable precursor B cell defects, indicating that signaling from the IL-7R(-/-) required this motif. Although the defect in IL-7R alpha(449F/449F) pro-B cells was associated with loss of STAT5 activation and diminished expression of Mcl1, this was not rescued by overexpression of Bcl-2. IL-7R alpha(449F/449F) and IL-7R alpha(-/-) pre-B cells also showed defective cyto-Igm and CD25 expression, associated with reduced levels of Rag1, Rag2, and Irf4. Pre-B cells from IL-7R alpha(449F/449F) mice also failed to proliferate, perhaps as a result of the failure to rearrange Ig mu. Our data suggest that IL-7R alpha Tyr(449) was essential for IL-7R alpha signaling in bone marrow B cell development and survival.

• 出版日期2014-10-1