Ectopic expression of CD127 restores the numbers of thymic and peripheral T cell populations in adenosine A2A receptor deficient mouse

Abstract

Abstract Inhibition of proximal TCR signals by adenosine A2A receptors (A2AR) is important for T cell development and maintaining T cell quiescence in vivo. Deletion of A2ARs causes accelerated growth of B16 and MB49 tumors, which is associated with reduced T cell accumulation in tumors and decreased CD127 expression and interleukin-7 responsiveness. Here we showed that ectopic expression of CD127 in A2AR deficient mice restores normal numbers of thymic populations and IL-7 responsiveness of T cells. Ectopic expression of CD127 in A2AR deficient mice also caused accumulation of similar numbers of T cells in the periphery as compared to A2AR proficient mice. Growth of B16 tumors in A2AR deficient mice was accelerated as compared to A2AR proficient mice. However, growth of B16 tumors was comparable between A2AR deficient or proficient mice ectopically expressing CD127. Adenosine A2A receptor deletion or ectopic CD127 expression did not change Vbeta selection suggesting changes in T cell repertoire may not be involved in increased tumor growth and reduced T cell numbers in A2AR deficient mice. Interestingly, tumor growth in A2AR and CD127 double deficient mice was slower as compared to CD127 deficient mice. Finally, adenosine preconditioning of engineered T cells significantly reduced lung colonization of B16OVA tumors and persistence of engineered T cells. Overall these results suggest that CD127 regulation by adenosine is important for T cell maintenance and functional responses in vivo and blockade of A2AR to improve anti-tumor immune responses should be further promoted by providing signals for T cell survival.