Department of Molecular Microbiology and Immunology
Oregon Health & Science University
This dissertation presents my studies investigating the delivery of CD40 ligand (CD40L, CD154) from helper T lymphocytes to antigen-presenting B lymphocytes. CD40L is a type two transmembrane TNF superfamily cytokine made by T cells that engages CD40 on antigen-presenting cells, including B cells, initiating downstream signaling resulting in B cell proliferation, differentiation, and antibody formation. Helper T cells can produce CD40L de novo upon antigen-specific interactions, but they also have an intracellular secretory compartment containing a small amount of preformed CD40L that is brought to the T cell surface rapidly upon antigen recognition. In the second chapter of the dissertation, I investigate the function of preformed CD40L in the absence of de novo CD40L. Preformed CD40L is capable of fulfilling some functions previously assumed to require de novo CD40L, including upregulation of costimulatory molecules, production of cytokines by DCs, and antigen-specific proliferation of B cells. Therefore, this secretory compartment of CD40L protein may play a significant role in the adaptive immune response, especially when T cell/APC interactions are brief and not long enough for de novo protein production. In Chapter 3 of this dissertation, I describe my novel finding that CD40L does not remain on the T cell surface but is actually transferred to antigen-presenting B cells. Transfer is much more efficient to antigen-bearing than to bystander B cells, a finding that may explain the phenomenon of affinity maturation of the antibody response, a process that is required for generation of the high affinity antibodies that protect us from infectious agents and their toxins. In the germinal center reaction, rare somatic mutant B cells with higher affinity for antigen are selected for survival and eventually exported as long-lived memory B cells and antibody secreting cells. Selection is known to depend on acquisition of limited survival signals from helper T cells. Transfer of CD40L proportional to the amount of antigen presented by individual B cells may allow T cells to selectively deliver a sustained signal required for survival of higher affinity mutant B cells. In the fourth Chapter of this dissertation, I investigate the functional significance of differences between the Th1 and Th2 helper T cell subsets in the segregation of molecules at the area of interaction between the helper T cells and APCs, called the immunological synapse. I found that despite distinct immunological synapse structures, preformed CD40L is delivered in an antigen-specific manner by both Th1 and Th2 helper T cells.
School of Medicine
Gardell, Jennifer L., "Directed delivery of CD40 ligand from helper T cells to antigen-presenting B cells" (2015). Scholar Archive. 3718.
Available for download on Sunday, September 16, 2018