Detail

The Covey lab focuses on defining parameters that lead to the differentiation of B cells into antibody-producing cells. We are particularly interested in understanding critical lymphocyte interactions that result in the diversification of B cell subsets and antibody classes during an ongoing immune response. We use a variety of molecular and cellular tools to study these interactions and utilize both mouse models and human immune cells in our work.

Our primary focus has been on characterizing the helper function exhibited by CD40L expressed on activated CD4 T cells with its cognate receptor CD40 expressed on antigen-activated B cells and other antigen presenting cells (APCs). We found that CD40L expression is regulated in activated CD4 T cells through transcriptional mechanisms as well as through an activation-induced pathway of mRNA instability that corresponds to the binding of an RNA complex nucleated by the multifunctional RNA protein, polypyrimidine tract binding protein 1 (PTBP1). To characterize the importance of this pathway during an immune response we have generated a strain of mice in which the PTBP1 stability element has been deleted from the CD40L gene (Fig. 1, termed CD40L-D5). Characterization of CD40L-D5 mice revealed normal development of lymphoid and myeloid subsets as well as B cell subsets in the spleen (Fig. 2). However, specific aspects of immunoglobulin production were deficient. These mutant mice are being used in a number of experiments to understand the requirement for ongoing T cell-B cell interactions for optimal antibody expression during an immune response.

A second area of investigation involves studying the CD40 pathway in chronic lymphocytic leukemia (CLL). CLL is a malignancy linked to the clonal expansion of small, mature CD5⁺ B cells in the blood, bone marrow and secondary lymphoid tissues. It is the most common adult leukemia in the United States and the disease is characterized by elevated blood lymphocyte counts, enlargement of lymph nodes, spleen, and liver, as well as anemia and decreased platelet counts. Although symptoms may be lessened with both chemotherapy and therapy targeting B cell receptor (BCR) signaling, currently no established treatment is curative for the majority of patients. Thus, new and innovative approaches are mandated to uncover novel targets that have the potential of being translated into future CLL treatments. We are using our understanding of CD40L-CD40 interactions to define characteristics of CD40-responsive versus-unresponsive CLL for the purpose of identifying novel biomarkers.  Our recent findings are supportive of those showing that separate CLL clones are heterogeneous with respect to CD40-dependency as shown by proliferation differences (Fig. 3) as well as by NF-kB activation and co-stimulatory molecule expression.