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. 2020 Apr 23;11:380. doi: 10.3389/fphys.2020.00380

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Copyright © 2020 Martínez-Méndez, Villarreal, Mendoza and Huerta.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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(A) The activation core of the network represents downstream signaling induced by TCR and CD28, encompassing the activity of CTLA-4, the anergy factor NDRG1, and the nutrient micro-environment-sensing protein AMPK. The effect of exogenous cytokines is not included. Green and red rectangles represents stimulatory and inhibitory nodes of the activation core, respectively. (B) Subnetwork of the core showing the convergence of the activity of NFκB, AP-1 and NFAT for the expression of the IL-2 gene (IL2G). IL2G induces the expression of its own high affinity receptor (CD25). CD25 mediates the activity of PDK1, mTOR, SOS, and STAT5, which positively feedback the expression of IL-2. The anergy-inducing factor Nrdg1 is induced by NFAT and inactivated by Akt. Colors of rectangles correspond to the type of components, as indicated in Figure 1.