Human immunoglobulin switch recombination in response to T cell-B cell interactions
Resting IgM+ B cells differentiate into antibody-producing cells of different immunoglobulin isotypes in response to a complex array of T cell interactions. Activation signals are mediated by specific T cell cytokines as well as by physical or cognate interactions between ligands, and their respective receptors, located on the surface of T and B cells. Our laboratory is focused on understanding how interactions at the surface of the B cell influence its differentiation into antibody-producing cells. Our assay for differentiation is transcriptional activation (I region transcription) and switch recombination of the heavy chain alleles of both transformed B cell clones and primary peripheral B cells from immunodeficient and control patients. For example, we have recently analyzed thelymphocyte function in a young girl with non-X-linked hyper-IgM syndrome. In analyzing CD40-mediated functions in the patient B cells we have identified a subset of functions that are affected by the immune defect. Most dramatically is a complete shutdown of transcriptional activation of the Ig genes after T cell stimulation. In addition, we found diminished CD23, and CD154 responses to CD40L and IL-4 (CD23) or T cell activation (CD154). We are trying to understand the basis for immune dysfunction and determine whether it resides with a factor that is integral to multiple signal transduction pathways in the B cell.
The second active area of research in my laboratory is identifying post-transcriptional mechanisms that regulate CD40 ligand (CD40L or CD154) expression. The necessity for strict regulation of CD154 expression may be potentially dictated by a need to limit the interaction of activated CD4+ T cells with non-selected B cells and other CD40-expressing cells during an immune response. We found that CD154 mRNA is regulated post-transcriptionally throughout a time course of a-CD3 or a-CD-3 + a-CD28 activation. Recently, we have identified a T cell activation-dependent complex (termed Complex I) that binds specifically to a region of the CD154 3'UTR and mediates message stability. We are interested in studying the expression of Complex I in T cells under different conditions of stimulation. We feel the regulated decay pathway of CD154 mRNA decay may be a novel. non-ARE pathway for regulating mRNA stability.