Activated Notch2 Potentiates CD8 Lineage Maturation and Promotes the Selective Development of B1 B Cells

Abstract

Although studies have shown that the Notch2 family member is critical for embryonic development, little is known concerning its role in hematopoiesis. In this study, we show that the effects of an activated form of Notch2 (N2IC) on the T-cell lineage are dosage related. High-level expression of N2IC results in the development of T-cell leukemias. In contrast, lower-level expression of N2IC does not lead to transformation but skews thymocyte development to the CD8 lineage. Underlying this skew is a dramatic enhancement in positive selection and CD8SP maturation. N2IC permits early B-cell development but blocks the maturation of conventional B2 cells at the pre-B stage, which is the limit of endogenous Notch2 protein expression in developing B cells. Most strikingly, while B2 B cell development is blocked at the pre-B-cell stage, N2IC promotes the selective development of LPS-responsive B1 B cells. This study implicates a role for Notch2 in the maturation of the CD8 lineage and suggests a novel function for Notch2 in the development of the B1 B-cell subset.

ACKNOWLEDGMENTS

We thank Lisa Jia and Larry Gartland for their invaluable technical help. We are particularly grateful to Casey Weaver for critical reading of the manuscript. We especially wish to thank Flavius Martin and John Kearney for their technical expertise and many helpful discussions.

This work was supported by a Howard Hughes faculty development award to C.A.K. (grant no. 53000281) and a Basic Mechanisms in Lung Disease Predoctoral Training grant to C.M.W (grant no. HL07553). Work by C.S.S. was supported by an Immunology Diseases and Basic Immunology postdoctoral training grant (grant no. AIT3207051).