CD73 is a membrane-bound enzyme catalyzing the final step of the conversion of extracellular ATP to adenosine, which then binds to its receptors and signals via cAMP and non-cAMP-mediated pathways. While CD45RBlow helper T cells from wild-type and CD73 KO mice were both highly enriched in the FoxP3+ regulatory T cell transcription factor, cells from CD73 KO mice produced more IFN-γ and IL-17A and could not inhibit effector T cell proliferation and function in vitro. In vivo CD73 expression by both regulatory (CD45RBlow) and effector (CD45RBhigh) T cells was required for Treg to prevent effector T cell-induced colitis following adoptive transfer into immunodeficient Rag1 KO recipients. The cytokine profile in the intestine was skewed compared to the protective combination of wild-type CD45RBlow and wild-type CD45RBhigh. Donor CD45RBlow recovered from colitic mice had reduced FoxP3 and CD45RBhigh phenotype shifted from Th17 to Th1. If recipients lacked both Rag1 and CD73, wild-type CD45RBlow Th cells did not protect from T cell-induced colitis. CD45RBlow Th cells lost FoxP3, acquired Th1 and Th17 transcription factors, depleted recipient’s innate lymphoid cells and caused disease. Prior adoptive transfer of innate lymphoid cells protected these recipients from disease and maintained FoxP3 expression on cells of the CD45RBlow pool. Thus, CD73 on cells of both adaptive and innate immunity is required for effective regulatory T cell function in intestinal homeostasis.
Background and Aims: Extracellular signaling molecules, such as anti‐inflammatory adenosine, play a major role in restraining immune response and protecting tissue from inflammatory damage. Adenosine is generated from the ATP through the action of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) that sequentially dephosphorylates ATP to ADP to 5’‐AMP, which is then catabolized to adenosine by ecto‐5'‐nucleotidase (CD73, Nt5e). The aim of this study was to investigate the role of extracellular adenosine in control of helper T cell (Th) cell differentiation and cellular function. Results: Adenosine levels were controlled with a pharmacological approach using the non‐hydrolysable adenosine analog, NECA. Naïve CD4+ T cells were differentiated in vitro in the presence or absence of NECA in selective culture conditions. The presence of NECA suppressed the production of IL‐17a in cells isolated from Th17 conditions. We then explored a genetic approach to control adenosine levels in vivo, using an adoptive transfer colitis model. According to the model, the transfer of CD4+CD45RBhi cells, a subset that contains largely T effector (Teff) cells, will induce colitis when transferred to Rag1‐/‐ mice. Colitis can be ameliorated with the co‐transfer of CD4+CD45RBlo, a cell population with a primarily regulatory phenotype. T cells were isolated from Nt5e‐/‐ mice to investigate the function of Th cells compromised in the ability to produce adenosine. In our adoptive transfer studies, CD73 on both Treg and T effector proved to be necessary for Treg to prevent Teff‐induced colitis. Conclusions: Adenosine signaling has the ability to restrain Th17 response during differentiation through the direct reduction of the production of the pro‐inflammatory cytokine IL‐17a. The ability to produce adenosine is essential for effective Treg activity and compromising the adenosine pool changes the differentiation patterns of Th cells causing excessive inflammatory activation and tissue damage. Grant Funding Source: Supported By: T32 Gastrointestinal Training Grant
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