Browsing by Subject "Adenosine Receptors"
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Item Open Access Molecular mechanisms of adenosine regulation of helper T cell responses(Bilkent University, 2017-05) Koyaş, AltayPolarizations of helper T cells into different functional subsets is important in order to influence the progression of immune-related diseases. One of the major outcomes in immune cell activation and generation of immunogenic response followed by TCR stimulation, is elevation of extracellular adenosine and upregulation of adenosine A2A receptors. Adenosine A2A receptor stimulation elevates intracellular cAMP to regulate helper T cell responses., Intracellular receptors of cAMP, PKA and EPAC proteins regulate cellular responses downstream of cAMP. In this study, we showed that adenosine differentially suppresses Th1 polarization rather than polarization of other functional T cell subsets. Adenosine signaling strongly decreased T cell accumulation in all the polarizing conditions except for Th2 condition. Adenosine-mediated decrease in T cell accumulation is associated with decreased proliferation and survival. PI3K-AKT pathway by targeting the Akt phospho-activation is one of the essential factors for regulation of immune response. One of the targets for Akt is Foxo1, which is inhibited by Akt phosphorylation. Foxo1 is known to suppress T cell proliferation and important in T cell trafficking and survival. Mechanistic studies have shown that adenosine signaling decreases the phosphorylation of Akt and Foxo1 molecules downstream of TCR. A Foxo1 inhibitor, AS1842856, reverses the reduction in T cell accumulation after adenosine receptor stimulation in particularly Th1 and Th17 conditions by increasing T cell survival in these conditions rather than T cell proliferation. Further studies using PKA and EPAC specific analogs indicated that both pathways may be required for adenosine mediated suppression of Th1 polarization; however, PKA pathway alone is largely responsible from inhibition of T cell proliferation. Results of this study have major implications to understand potential cell-intrinsic effects of one of the major immunoregulatory pathways.Item Open Access Targeting adenosine receptors to improve vaccine efficacy(Bilkent University, 2016-12) Savaş, Ali CanVaccination is the major protection method against many diseases caused by pathogens through creating acquired immunity. Vaccines can be classified in two major groups, which are subunit vaccines and attenuated vaccines. Attenuated vaccines can create effective immunity however; they also can induce many different side effects such as fever and allergic reactions. On the contrary, with subunit vaccines side effects are decreased but the efficacy of the vaccines is also decreased and there is a need for repetitive vaccinations to provide long lasting immunity. That is why, there is a need for developing more efficient vaccines and particularly vaccine adjuvants. Adenosine receptors, as part of purinergic signaling, have a regulatory role in immune system. Adenosine and 4 different adenosine receptors have an immunosuppressive role in major immune cells to create acquired immunity such as DCs, macrophages and lymphocytes. That is why, we hypothesize that, the efficacy of vaccines can be decreased by endogenous adenosine and the usage of antagonists in adjuvant formulations can increase this efficacy by inhibiting the suppressive effects caused by endogenous adenosine. To be able to test this hypothesis, we first determine the specific adenosine receptor and antagonists taking a role in this immunosuppressive effect. For this purpose, we use primary dendritic cells and macrophages. We see that A2A and A2B receptors create most effective immunosuppression and SCH 58261 (A2A antagonist) and PSB 603 (A2B antagonist) are the main antagonists taking a role in the inhibition of this suppression. We then evaluated these two molecules in a vaccine formulation comprising MPL-A and AddaVax. As a result, these antagonists do not significantly change the general initial immune responses significantly however they create more antigen specific response. On the other hand, after antigen re-stimulation, mice taking these antagonists shows more antigen specific response and they also create higher antibody titers. With this study, adenosine receptor antagonists used in adjuvant formulations for the first time and it was shown that, with more study, they can be important in increasing vaccine efficacy created by immunostimulatory adjuvants.