Lack of Sprouty 1 and 2 enhances survival of effector CD8 ⁺ T cells and yields more protective memory cells

Abstract

Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8 T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8 T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic β-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8 T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong. Spry1/2 DKO LCMV gp33-specific P14 CD8 T cells survive contraction better than WT cells and generate significantly more polyfunctional memory T cells. The larger number of Spry1/2 DKO memory T cells displayed enhanced infiltration into infected tissue, demonstrating that absence of Spry1/2 can result in increased recall capacity. Upon adoptive transfer into naive hosts, Spry1/2 DKO memory T cells controlled infection better than WT cells. The enhanced formation of more functional Spry1/2 DKO memory T cells was associated with significantly reduced mTORC1 activity and glucose uptake. Reduced p-AKT, p-FoxO1/3a, and T-bet expression was also consistent with enhanced survival and memory accrual. Collectively, loss of Spry1/2 enhances the survival of effector CD8 T cells and results in the formation of more protective memory cells. Deleting Spry1/2 in antigen-specific CD8 T cells may have therapeutic potential for enhancing the survival and functionality of effector and memory CD8 T cells in vivo.

The Sprouty/Spred family as tumor suppressors: Coming of age

“…Furthermore, the importance of Sprouty expression appears to be dependent on oncogenic Ras mutations in certain tumors . In addition, the expression of the Sprouty/Spred family in CD8 + T cells might contribute to the suppression of antitumor immunity . Therefore, when the Sprouty/Spred family is targeted in cancer therapy, these should be taken into consideration to avoid unexpected results of the targeted therapy.…”

“…29 It has recently been reported that the loss of Sprouty1 and Sprouty2 promotes the survival of effector CD8 + T cells, resulting in the formation of more protective memory CD8+ T cells. 30 Another study has shown that Spred1 is upregulated in CD8 + tumorinfiltrating lymphocytes in a TGFβ-dependent manner. 31 These findings implicate the Sprouty/Spred family as the new potential targets in cancer immunotherapy.…”

Sprouty branches out to control T cell memory

“…Studies interrogating the regulation of TCRcoupled 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).…”

“…To date, the role of the Spry proteins in CD8 + effector T cell (Teff) responses and memory development is unknown. Shehata et al (2) show that the genes encoding Spry1 and Spry2, but not Spry3 and Spry4, are up-regulated in activated CD8 + T cells and memory subsets, suggesting that Spry1/2 may be the critical regulators of CD8 + T cells. To begin investigating the role of Spry1/2 in CD8 + Teff responses, Shehata et al induced type 1 diabetes in rat insulin promotermembrane-bound ovalbumin (mOVA) mice, which express OVA protein on pancreatic cells, by the adoptive transfer of naïve OVA-specific (OT-I TCR transgenic) CD8 + T cells.…”

“…Activation markers and chemokine receptors, such as CXCR3, CD43, and CD27, further subdivide the T EM and T CM CD8 + memory subsets (7), where the CD27 lo CD43 lo CD8 + memory subset mediates rapid protective immunity against bacterial or viral challenges despite having reduced proliferation and survival compared with the CD27 hi CD43 lo CD8 + memory subset (8,9). Shehata et al (2) found that, in the absence of Spry1/2, the expansion of memory CD8 + T cells, including the CD27 lo CD43 lo subset, provided better protection against secondary challenge. Therefore, targeting Spry1 and Spry2 may confer selective therapeutic potential by enhancing CD8 + T cell memory responses.…”