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The Journal of biological chemistry v.292 no.4, 2017년, pp.1211 - 1217   SCI SCIE
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The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center

Abbott, Robert K. (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Silva, Murillo (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Labuda, Jasmine (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Thayer, Molly (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Cain, Derek W. (the Duke Human Vaccine Institute, Duke University, Durham, North Carolina 27710 ); Philbrook, Phaethon (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Sethumadhavan, Shalini (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Hatfield, Stephen (From the New England Inflammation and Tissue Protection Institute, Northeastern University, Boston, Massachusetts 02115 and ); Ohta, Akio (From the New England Inflammation an ); Sitkovsky, Michail ( );
  • 초록  

    T follicular helper (T FH ) 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, G s 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 T FH frequency and function, and also promotes immunosuppressive T follicular regulatory cells (T FR ). 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 T FH to T FR 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 G S 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.


  • 주제어

    adenosine .   adenosine receptor .   cyclic AMP (cAMP) .   hypoxia .   vaccine .   vaccine development .   A2a adenosine receptor (A2aR) .   T follicular helper (TFH) cell .   T follicular regulatory (TFR) cell .   germinal center (GC) .   class switch recombination (CSR).  

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