AMBRA1 controls antigen-driven activation and proliferation of naive T cells

Abstract

AMBRA1 is a member of the BECN1 (BECLIN1) complex protein, and it plays a role in autophagy, cell death, tumorigenesis, and proliferation. We recently reported that on TCR stimulation, AMBRA1 controlled both autophagy and the cell cycle with metabolic regulation. Accumulating evidence has shown that autophagy and metabolic control are pivotal for T cell activation, clonal expansion, and effector/memory cell fate decision. However, it is unknown whether AMBRA1 is involved in T cell function under physiological conditions. We found that T cells in Ambra1-conditional knockout (cKO) mice induced exacerbated graft versus host response when they were transplanted into allogeneic BALB/c mice. Furthermore, Ambra1-deficient T cells showed increased proliferation and cytotoxic capability towards specific antigens in response to in vivo stimulation using allogeneic spleen cells. This enhanced immune response mainly contributed to naïve T cell hyperactivity. The T cell hyperactivity observed in this study were similar to those in some metabolic factor-deficient mice, but not those in other pro-autophagic factor-deficient mice. Under the static condition, however, naïve T cells were reduced in Ambra1-cKO mice, as same as in pro-autophagic factor-deficient mice. Collectively, these results suggested that AMBRA1 was involved in regulating T cell-mediated immune responses through autophagy-dependent and -independent mechanisms.

AMBRA1 and its role as a target for anticancer therapy

“…found that AMBRA1 regulates the activity of OVA53 precursor T cells and naive T cells in an autophagy-dependent manner ( 91 ). Furthermore, this group also found that AMBRA1 regulates the proliferation of precursor T cells and naive T cells in an autophagy-independent manner ( 92 ). This regulation might be attributed to the recent finding that CULLIN4–AMBRA1 E3 ligase regulates the stability of cyclin D to control the cell cycle ( 35 ).…”