Common γ-chain cytokine signaling is required for macroautophagy induction during CD4⁺ T-cell activation

Abstract

Abbreviations: ATG, autophagy-related; IFN, interferon; IL, interleukin; JAK, Janus kinase; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MTOR, mechanistic target of rapamycin (serine/threonine kinase); NL, ammonium chloride and leupeptin; PtdIns3K, class-III phosphatidylinositol 3-kinase; RPS6KB/p70S6K, ribosomal protein S6 kinase; 70kDa STAT, signal transducer and activator of transcription; TCR, T cell receptor; T H , T helper cell; Vb, vinblastineMacroautophagy is a cellular process that mediates degradation in the lysosome of cytoplasmic components including proteins and organelles. Previous studies have shown that macroautophagy is induced in activated T cells to regulate organelle homeostasis and the cell's energy metabolism. However, the signaling pathways that initiate and regulate activation-induced macroautophagy in T cells have not been identified. Here, we show that activation-induced macroautophagy in T cells depends on signaling from common g-chain cytokines. Consequently, inhibition of signaling through JAK3, induced downstream of cytokine receptors containing the common g-chain, prevents full induction of macroautophagy in activated T cells. Moreover, we found that common g-chain cytokines are not only required for macroautophagy upregulation during T cell activation but can themselves induce macroautophagy. Our data also show that macroautophagy induction in T cells is associated with an increase of LC3 expression that is mediated by a posttranscriptional mechanism. Overall, our findings unveiled a new role for common g-chain cytokines as a molecular link between autophagy induction and T-cell activation.

Key roles of autophagy in regulating T‐cell function

“…In fact, knocking down JNK1 or JNK2 in Th1 cells has been shown to reduce the number of LC3‐positive vesicles . In line with these results, at least two proteins that form part of the PI3KC3 complex are required for LC3 conjugation in CD4 + T cells: Vps34‐ as well as Beclin1‐deficient T cells show reduced macroautophagy activity following TCR and CD28 stimulation .…”

“…Several studies have shown that TCR engagement in CD4 + and CD8 + T cells induces macroautophagy . Full activation of T cells requires TCR engagement together with costimulatory molecules and cytokine signaling.…”

“…Inhibition of mTOR signaling by rapamycin during T‐cell activation was shown to not only result in defective cellular activation but to also induce anergy . Therefore, T‐cell activation introduces a paradigm of concomitant activation of mTOR, a negative regulator of macroautophagy , together with macroautophagy induction in human and murine T cells . A recent study has identified that TNF‐α induced protein 3 (TNFAIP3) restricts mTOR activity and promotes macroautophagy and survival in CD4 + T cells .…”

“…A recent study has identified that TNF‐α induced protein 3 (TNFAIP3) restricts mTOR activity and promotes macroautophagy and survival in CD4 + T cells . However, the fact that activated T cells activate mTOR and upregulate macroautophagy, and that inhibition of mTOR with rapamycin has little effect on activation‐induced macroautophagy in CD4 + T cells, supports that induction of macroautophagy in response to TCR engagement is likely induced in an mTOR‐independent manner . Macroautophagy induction might instead involve Jun kinase (JNK), which in human epithelial cell lines has been shown to phosphorylate B‐cell lymphoma 2 and cause its dissociation from Beclin1, which then becomes able to interact with Vps34‐Vps15‐ATG14 in the PI3KC3 complex to induce autophagosome formation (Fig.…”

“…Cytokine signaling plays a major role in the regulation of T‐cell function in both naive and effector T cells. Our laboratory has shown that signaling through common gamma‐chain cytokine receptors, such as the IL‐2 receptor, induces macroautophagy in CD4 + T cells; and that this pathway is required to maintain a high macroautophagy flux in activated T‐helper cells . In CD4 + T cells, IL‐2 is secreted early after TCR engagement and is crucial for sustained proliferation and survival, as well as for effector differentiation and memory programming.…”