Abstract
T follicular helper (TFH) cells have been shown to be critically required for the germinal center (GC) reaction where B cells undergo class switch recombination and clonal selection to generate high affinity neutralizing antibodies. However, detailed knowledge of the physiological cues within the GC microenvironment that regulate T cell help is limited. The cAMP-elevating, Gs protein-coupled A2a adenosine receptor (A2aR) is an evolutionarily conserved receptor that limits and redirects cellular immunity. However, the role of A2aR in humoral immunity and B cell differentiation is unknown. We hypothesized that the hypoxic microenvironment within the GC facilitates an extracellular adenosine-rich milieu, which serves to limit TFH frequency and function, and also promotes immunosuppressive T follicular regulatory cells (TFR). In support of this hypothesis, we found that following immunization, mice lacking A2aR (A2aRKO) exhibited a significant expansion of T follicular cells, as well as increases in TFH to TFR ratio, GC T cell frequency, GC B cell frequency, and class switching of GC B cells to IgG1. Transfer of CD4 T cells from A2aRKO or wild type donors into T cell-deficient hosts revealed that these increases were largely T cell-intrinsic. Finally, injection of A2aR agonist, CGS21680, following immunization suppressed T follicular differentiation, GC B cell frequency, and class switching of GC B cells to IgG1. Taken together, these observations point to a previously unappreciated role of GS protein-coupled A2aR in regulating humoral immunity, which may be pharmacologically targeted during vaccination or pathological states in which GC-derived autoantibodies contribute to the pathology.
Highlights
T follicular helper (TFH) cells have been shown to be critically required for the germinal center (GC) reaction where B cells undergo class switch recombination and clonal selection to generate high affinity neutralizing antibodies
In support of this hypothesis, we found that following immunization, mice lacking A2a adenosine receptor (A2aR) (A2aRKO) exhibited a significant expansion of T follicular cells, as well as increases in TFH to T follicular regulatory cells (TFR) ratio, GC T cell frequency, GC B cell frequency, and class switching of GC B cells to IgG1
T Follicular Cells Have the Potential to Generate Extracellular Adenosine and Express Functional A2aR—To ascertain whether the GC comprises regions of high extracellular adenosine, we looked for a proxy for adenosine generation as direct measurement of exAdo via equilibrium microdialysis probes is not technically feasible
Summary
The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center*□S. T follicular helper (TFH) cells have been shown to be critically required for the germinal center (GC) reaction where B cells undergo class switch recombination and clonal selection to generate high affinity neutralizing antibodies. Injection of A2aR agonist, CGS21680, following immunization suppressed T follicular differentiation, GC B cell frequency, and class switching of GC B cells to IgG1 Taken together, these observations point to a previously unappreciated role of GS protein-coupled A2aR in regulating humoral immunity, which may be pharmacologically targeted during vaccination or pathological states in which GC-derived autoantibodies contribute to the pathology. In excellent correlation with these determinations, we found that pharmacological stimulation of the A2aR from days 2 to 8 following primary vaccination led to significant decreases in the frequency of GC B cells and T follicular cells as well as reduced class switching of GC B cells to IgG1
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