Abstract
Autophagy plays a central role in maintaining T cell homeostasis. Our previous study has shown that hepatocyte-specific deficiency of receptor for activated C kinase 1 (RACK1) leads to lipid accumulation in the liver, accompanied by impaired autophagy, but its in vivo role in T cells remains unclear. Here, we report that mice with T cell-specific deletion of RACK1 exhibit normal intrathymic development of conventional T cells and regulatory T (Treg) cells but reduced numbers of peripheral CD4+ and CD8+ T cells. Such defects are cell intrinsic with impaired mitochondrial clearance, increased sensitivity to cell death, and decreased proliferation that could be explained by impaired autophagy. Furthermore, RACK1 is essential for invariant natural T cell development. In vivo, T cell-specific loss of RACK1 dampens concanavalin A-induced acute liver injury. Our data suggest that RACK1 is a key regulator of T cell homeostasis.
Highlights
T cells are crucial controllers of inflammation and immunity against pathogens and incipient tumors
Specific inactivation of receptor for activated C kinase 1 (RACK1) in T cells was first achieved by crossing mice homozygous for a Gnb2l1 conditional allele (Gnb2l1F/F) with mice expressing a transgene encoding Cre recombinase driven by the lymphocyte-specific protein tyrosine kinase (Lck) proximal promoter [17]
Comprehensive analyses of T cell production in the thymus revealed that the percentages and absolute numbers of double negative (DN), double positive (DP), and single positive (SP) CD4+ and CD8+ thymocytes appeared to unaltered in Gnb2l1F/F; lck-Cre mice compared with littermate controls (Figure 1B)
Summary
T cells are crucial controllers of inflammation and immunity against pathogens and incipient tumors. As an evolutionarily conserved eukaryotic process, autophagy degrades long-lived proteins and other cytoplasmic contents such as aggregated proteins, damaged/excess organelles, and lipids through lysosomes [10,11,12]. T cell-specific deletion of autophagy-related genes Atg, Atg, Atg, Atg16l1, Vps, or Beclin 1 leads to decreased frequencies and numbers of peripheral CD4+ and CD8+ T cells [1,2,3,4,5,6,7,8,9]. The clearance of damaged/excess organelles, especially mitochondria, is suggested to be the key mechanism by which autophagy promotes the survival of peripheral T lymphocytes [2,3,4, 6]. Previous results have indicated that Atg3-, Atg5-, Atg7-, or Vps34-deficient T cells cannot proliferate efficiently [2,3,4, 8, 9]
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