Autophagy is essential for ER homeostasis and calcium mobilization in T lymphocytes (35.13)

Abstract

Abstract The evolutionarily conserved intracellular bulk degradation pathway, macroautophagy, is involved in eliminating intracellular pathogens, endogenous antigen presentation in MHC-II pathway and T lymphocytes homeostasis. However, the underlying mechanisms by which autophagy regulates T lymphocyte function remain unknown. Here we used autophagy related protein 7 (Atg7) conditional knockout mice to investigate these mechanisms. Comparing to wild type T cells, Atg7-deficient T cells displayed impaired calcium influx upon TCR triggering or lower concentration of ionomycin stimulation. However, the proximal signaling of TCR in Atg7-deficient T cells was intact. The calcium influx defect in Atg7-deficient T cells may be related to an abnormal expansion of endoplasmic reticulum (ER) and higher intracellular calcium stores. We found that higher amount of ionomycin or the ER sarco/endoplasmic reticulum Ca2+ATPase (SERCA) pump inhibitor, thapsigargin, could rescue the calcium influx defect in Atg7-deficient T lymphocytes. Atg7-deficient T cells failed to efficiently proliferate and were blocked at S phase when stimulated by TCR or PMA plus ionomycin respectively. In contrast, Atg7-deficient T cells were fully activated and capable of secreting IL-2. Our results suggest that an important role for autophagy in T cells is to maintain ER homeostasis.