The costimulation-regulated duration of PKB activation controls T cell longevity

Abstract

A brief antigenic stimulus can promote T cell proliferation, but the duration and nature of intracellular signals required for survival are unclear. Here we show that in the absence of OX40 costimulation, antigen-activated CD4+ cells are short-lived because the activity of protein kinase B (PKB; also known as Akt) is not maintained over time. Activated T cells that express a dominant-negative variant of PKB also undergo apoptosis, reproducing the OX40-deficient phenotype. In contrast, an active form of PKB prevents downregulation of antiapoptotic proteins in OX40-deficient T cells, rescues antigen-induced cell survival in vivo, and controls inflammation in recall responses. Thus, sustained and periodic PKB signaling has an integral role in regulating T cell longevity.

Intracellular Signals of T Cell Costimulation

“…TRAFs mediate OX40 signals via NF-κB-inducing kinase (NIK) that activate noncanical NF-κB activation, a PI3K-independent pathway (31). In addition, several groups reported that OX40 signals could sustain PI3K/PKB activities, which may also impact on canonical NF-κB activation (15,16). More importantly, recent data directly showed that OX40 signaling could target the NF-κΒ1 pathway in peripheral antigen-responding CD4 T cells.…”

“…However, the mechanism of how costimulation regulates T cell proliferation is still unclear. The enhanced proliferation mediated by costimulation is strongly correlated with the increased cytokine secretion, i.e., IL-2 and IL-12, which promote T cell proliferation (12,15,58).…”

“…OX40 regulates T cell survival by sustaining PKB mediated expression of bcl-2 and bcl-xL (15,76). Upon interaction with its ligand--OX40L, the cytoplasmic tail of OX40 associates with an adapter protein TRAF2 (79) to mediate signal transduction, probably through PI3K/PKB/ NF-κB pathway then regulates expression of bcl-xL, A1, and bcl-2 that controls T cell longevity (4).…”

“…Similarly, OX40 ligand (OX40L) is another TNF family member, which is expressed on APCs hours or days after activation. T cells lacking OX40 keep dividing initially but their ability of dividing diminishes over time and eventually die (15)(16)(17) .…”

The role of apoptosis in the development and function of T lymphocytes

“…OX40 -/-T cells have a defect in long term survival. This survival defect is rescued by retrovirus mediated overexpression of Bcl-2, Bcl-x L or activated Akt kinase [232,233]. OX40L is detected on activated B cells, macrophages and dentritic cells [234].…”