Sprouty branches out to control T cell memory

Abstract

CD8+ T cells provide critical immune protection against infections and cancer. Upon T cell receptor (TCR) recognition of a cognate antigen–MHC I complex and costimulatory signals presented by dendritic cells, quiescent CD8+ T cells undergo activation, leading to proliferation and effector responses that mediate clearance of pathogen-infected cells or cancer. During the effector stage, some CD8+ T cells are short-lived effectors (KLRG1hi CD127lo), while others differentiate into memory precursors (MP) (KLRG1lo CD127hi) with the potential to develop into long-lived memory cells (1). The development of memory CD8+ T cells is an essential component of protective immunity. Studies interrogating the regulation of TCR-coupled intracellular signaling pathways have provided important insight into the mechanisms controlling T cell activation, function, and effector and memory fate decisions. In PNAS, Shehata et al. (2) demonstrate that the signaling molecules Sprouty 1 and Sprouty 2 (Spry1/2) antagonize TCR-mediated signaling through Akt–FoxO1/3a and limit CD8+ MP and subsequent memory formation (Fig. 1). Fig. 1. Spry1/2 limit CD8+ T cell memory development through regulating the mTOR–Akt–FoxO signaling axis. In T cells, Akt activation is mediated by phosphorylation at Thr308 (TCR/costimulation-PI3K–dependent) and Ser473 (mTORC2-dependent). Active Akt promotes mTORC1 and inhibits FoxO1/3a. FoxO1 is an important positive regulator of CD8+ T cell memory development, while mTORC1 and mTORC2 are both negative regulators. Spry1/2 impair CD8+ T cell memory formation, partially through the regulation of mTOR–Akt–FoxO signaling, and potentially AMPK. LAT, linker for activated T cells; PLC-γ, phospholipase C-γ. Spry1/2 are two members of the conserved Spry family originally … [↵][1]1To whom correspondence should be addressed. Email: hongbo.chi{at}stjude.org. [1]: #xref-corresp-1-1