Résumé : In this work, we were interested in studying the effect of two main metabolic factors, hypoxia and extracellular ATP metabolism, on the effector function of T helper subsets. The major oxygen sensor is HIF-1α which is continuously degraded in the presence of oxygen but is stabilized in hypoxia, leading to transcription of genes involved in cellular adaptation to low oxygen level. Our data show that the proportion of IFN--producing Th1 cells was strongly decreased in hypoxia, as compared to normoxia. The proportion of IL-17-producing cells was increased in hypoxia, whereas the proportion of Foxp3+ T cells decreased dramatically. The changes in the proportion of Th1, Th17 and Treg cells were abolished in HIF-1α-deficient cells. Our data highlight a role for STAT3, SOCS3 and IL-10 and suggest that STAT3 activation in hypoxia results from decreased expression of SOCS3, a negative feedback regulator of STAT3. We conclude that hypoxia reinforces the IL-10-induced negative feedback mechanism, thereby preventing excessive Th1 responses.

In the second part of this work, we investigated the role of the adenosinergic regulation in intestinal homeostasis in mice in steady state conditions and upon acute infection with Toxoplasma gondii. We showed that most CD4 T cells (expressing or not Foxp3) in the gastrointestinal tract are well equipped to metabolize extracellular ATP (that is released by commensal bacteria) and generate immunosppressive adenosine. Interestingly, CD73 expression was downregulated during acute infection with T. gondii and administration of adenosine receptor agonists limited immunopathology, suggesting that activation of adenosine receptors may constitute an efficient approach to control intestinal inflammation.

Hypoxia and the adenosinergic pathway represent two regulatory mechanisms which can control inflammation and prevent host damage, but may also have undesirable effects in tumors by impeding immune resistance.