CD19 affects B-cell lymphopoiesis at multiple stages influencing survival, proliferation and differentiation of developing B-cells.

摘要

My thesis is focused on the role of CD19 in regulation of B-cell fate. Cell fate decisions occur throughout B-cell development and determine the composition of the B-cell pool. Autoimmunity is prevented by the removal of self-reactive B-cells while immunity to foreign antigens can still be provided. B-cell development occurs in ordered stages, the result of which are cells expressing functional antigen receptor (B-cell receptor; BCR). Positive and negative selection occur at points when the BCR is expressed on the cell surface, such as the immature B-cell stage in the bone marrow. During each of these phases CD19 is associated with the antigen receptor and is modulating signals from the BCR. My projects involved determining the stage at which and the extent to which CD19 contributes to early B-cell development, and how CD19 signaling at later stages of development may result in distinct cell fates.;Using bone marrow chimeras and cell transfer techniques I have found that CD19 is necessary for providing survival signals needed for the maintenance of mature B-cells. From biochemical experiments I found that CD19 is important for activation of the serine/threonine kinase, AKT, a kinase that has been shown to promote survival in many cell lines. In addition, I have found that CD19 is important for proliferation in early B-cell development. Of importance is its role at the pre-B cell stage where signals by the pre-BCR result in proliferative expansion of cells with functional heavy chain gene rearrangements. In these ways CD19 mirrors the B-cell receptor in that it has variable roles at different stages of development. At early stages it promotes proliferation, at later stages it is important for survival, and at multiple stages its major role is in promoting differentiation.