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Inhibition of regulatory T cell proliferation by cAMP: a role for Epac1

Bijlsma, K.T. (2011) Inhibition of regulatory T cell proliferation by cAMP: a role for Epac1. Bachelor's Thesis, Biology.

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Background: Regulatory T lymphocytes (Tregs) play an important role in the peripheral tolerance, by suppressing autoreactive T cells. By maintaining the peripheral tolerance, Tregs control autoimmune and allergic diseases (Sakaguchi, 2004). Cyclic adenosine monophosphate (cAMP) is currently believed to inhibit proliferation in T cells via the major cAMP effector protein kinase A (PKA) and the novel cAMP effector exchange protein directly activated by cAMP (Epac1 and Epac2). Though inducible regulatory T cells (iTregs), a subpopulation of regulatory T cells, bare high concentrations of cAMP and proliferation is not suppressed. The T cell proliferation inducer interleukin-2 (IL-2) is highly expressed in iTregs, and that might cause the insensitivity of iTregs to cAMP with regard to its inhibition of proliferation. Here we studied the expression of Epac1 and Epac2 in iTregs. In addition we analysed acute effects of cAMP analogs on early signaling in iTregs. Methods: We used human CD4+ T cells that were differentiated into iTregs and control cells, T effector cells (Teffs). The cells were stimulated with Epac-activator 8-pCPT-2’-O-Me-cAMP and PKA-activator 6-Bnz-cAMP. The activation of vasodilator-stimulated phosphoprotein (VASP) was analyzed to validate the specificity of the activators. The activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was analyzed as an indicator of proliferation. The cells were treated with IL-2 and analyzed for the expression of Epac1 and Epac2. Results: 6-Bnz-cAMP activates VASP in both iTregs and Teffs, which correspond with expected specificity. Altered levels of activated ERK1/2 were observed in both iTregs and Teffs after stimulation with 8-pCPT-2’-O-Me-cAMP or 6-Bnz-cAMP. Epac1 is lower expressed in iTregs and the expression of Epac2 is downregulated by IL-2 in both iTregs and Teffs. Conclusion: Activation of VASP by 6-Bnz-cAMP displays the specificity of the analogs in this experiment. iTregs seem to be insensitive to cAMP, most likely due to their low levels of Epac1. IL-2 downregulates Epac2 in both Teffs and iTregs.

Item Type: Thesis (Bachelor's Thesis)
Degree programme: Biology
Thesis type: Bachelor's Thesis
Language: English
Date Deposited: 15 Feb 2018 07:46
Last Modified: 15 Feb 2018 07:46

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