title: The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center.
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, Gsprotein-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 TFHfrequency 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 TFHto TFRratio, 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 GSprotein-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.
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and robertkabbott@gmail.com.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Abbott
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Murillo
authors.initials: M
authors.lastname: Silva
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Jasmine
authors.initials: J
authors.lastname: Labuda
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Molly
authors.initials: M
authors.lastname: Thayer
authors.affiliation: the Duke Human Vaccine Institute, Duke University, Durham, North Carolina 27710.
authors.forename: Derek W
authors.initials: DW
authors.lastname: Cain
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Phaethon
authors.initials: P
authors.lastname: Philbrook
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Shalini
authors.initials: S
authors.lastname: Sethumadhavan
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hatfield
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and.
authors.forename: Akio
authors.initials: A
authors.lastname: Ohta
authors.affiliation: From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and m.sitkovsky@neu.edu.
authors.forename: Michail
authors.initials: M
authors.lastname: Sitkovsky
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D018858:Germinal Center / Q000276:immunology*; D056724:Immunity, Humoral; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000276:immunology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010627:Phenethylamines / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D010627:Phenethylamines; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D000241:Adenosine
keywords: A2a adenosine receptor (A2aR); T follicular helper (TFH) cell; T follicular regulatory (TFR) cell; adenosine; adenosine receptor; class switch recombination (CSR); cyclic AMP (cAMP); germinal center (GC); hypoxia; vaccine; vaccine development