Most vaccines confer immunity through induction of neutralizing antibody. Successful prophylactic vaccination induces durable antibody titers and a memory B cell pool that can rapidly secrete high-affinity antibody upon encounter with pathogens. CD4 T cells are essential for enhanced secondary antibody responses both by controlling the formation of memory B cells and by providing rapid T cell help to activated memory B cells and promote their differentiation into antibody-secreting cells (ASCs). It is well-established that memory B cells are most often formed within germinal centers (GCs), a lymphoid microenvironment that is reliant on the helper activity follicular helper CD4 T (Tfh) cells. Tfh cells can be classified into pre-Tfh cell and GC Tfh cell subsets. Pre-Tfh cells accumulate at the T-B follicular border where cognate interaction with recently-activated B cells re-enforces high Bcl-6 expression through SAP and ICOS signaling to drive further differentiation to GC Tfh cells. Bcl-6 is considered to be a master transcriptional regulator of Tf differentiation and expression correlates with up-regulation of CXCR5 on CD4 T cells. It is not understood how Tfh cells, either as pre-Tfh or GC Tfh cells, regulate the differentiation of memory B cells from precursors. There is also a crucial role for a GC-homing subset of memory CD4 T cells that efficiently provide help to recently-activated B cells in the form of cytokines an co-stimulatory cell-cell contact in a manner similar to Tfh cells. Using a conditional mouse model developed in our lab we have identified a previously unknown function for the c-Myb transcription factor in CD4 T cells that support memory B cell responses. We find mice that contain c-Myb-deficient peripheral CD4 T cells produce severely diminished recall ASC responses, suggesting that c-Myb in CD4 T cells is an important regulator of immunological memory. Adoptive transfer experiments demonstrate that c-Myb in CD4 T cells is crucial for the development of high affinity memory B cells. Preliminary data demonstrate that mice with Myb-/- CD4 T cells have substantially fewer B cells and CD4 T cells that bear markers characteristic of memory cells as well as fewer Tfh cells and GC B cells after immunization. We hypothesize that c-Myb is required in CD4 T cells for development of memory B cells or for supporting differentiation of ASCs from memory B cells after secondary encounter with antigen (Ag), or for both. Defining the activity of c-Myb in CD4 T cells that support recall antibody production has significant implications for vaccine design. The factors that determine the effectiveness and durability of protection afforded by different vaccines are not fully understood and could be influenced by qualitative or quantitative properties of memory cells. Moreover, the potential of c- Myb to control antibody secretion from memory B cells that are specific for autoantigens (through regulation by cognate CD4 T cells) could have impact on our understanding of the pathogenesis of autoimmune disease. The overall goal of this proposal is to understand the requirements for c-Myb in CD4 T cell subsets that support generation of recall antibody production from Ag-specific B cells.

Public Health Relevance

Effective vaccines are lacking against a number of important human pathogens such as Plasmodium species, HIV and Bacillus anthracis. In addition, therapies for autoimmune diseases such as multiple sclerosis and systemic lupus erythematosus are not completely effective in ameliorating disease. These clinical problems involve the generation of recall antibody responses from memory B cells that are regulated by CD4 T cells, a process that is poorly understood. This project will contribute to our understanding of immunological memory by investigating how the c-Myb transcription factor regulates CD4 T cells that control recall antibody responses.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
High Priority, Short Term Project Award (R56)
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Cellular and Molecular Immunology - B Study Section (CMIB)
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Ferguson, Stacy E
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University of Virginia
Schools of Medicine
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