Antibodies are an important immune mechanism for clearing most viruses and long-lived antibodies form the functional basis of all currently used vaccines. Long-lived anti-viral antibody responses are generated via interactions between virus-specific B cells and virus-specific T follicular helper (Tfh) cells, which are a novel subset of CD4+ T cells that preferentially express CD40 ligand and IL-21 - factors that promote B cell proliferation and differentiation. Although the production of long-lived antibody responses requires help from Tfh cells, the factors that control Tfh differentiation are poorly understood. Our preliminary data demonstrate that high levels of IL-2 inhibit the differentiation of Tfh cells. Therefore, we hypothesize that the mechanisms that control IL-2 production, IL-2 signaling and IL-2 availability will also control the differentiation of Tfh cells and either promote or prevent anti-viral antibody responses. The experiments in Project 1 will determine how the persistence of viral antigen, the availability and type of costimulation, and the production and availability of IL-2 regulate T follicular helper differentiation and thus control long-lived antibody responses. Experiments in Aim 1 will test whether different types of virus infection (chronic-systemic, acute-systemic or acute-local) alter TCR signaling, IL-2 receptor expression and IL-2 production and thus, lead to changes in Tfh differentiation and antibody responses. Experiments in Aim 2 will test whether changes in costimulation or the expression of costimulatory receptors alter IL-2 production and Tfh differentiation. Experiments in Aim 3 will test whether external factors, such as IL-2 consumption by Tregs, alter IL-2 availability and control Tfh differentiation and antibody production.
Antibodies are important for the clearance of most viruses and are the functional basis of all currently used vaccines. Although the production of long-lived antibody responses requires help from T follicular helper cells, the factors that control the differentiation of T follicular helper cells are poorly understood. The experiments in Project 1 will determine how the persistence of antigen, the availability and type of costimulation, and the production and availability of IL-2 regulate T follicular helper differentiation and thus control long-lived antibody responses.
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