Growth Arrest-Specific 6 Enhances the Suppressive Function of CD4⁺CD25⁺Regulatory T Cells Mainly through Axl Receptor

Abstract

Background. Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs. Methods. The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR. Then, TAM receptors were silenced using targeted siRNA or blocked with specific antibody. The suppressive function of Tregs was assessed by using a CFSE-based T cell proliferation assay. Flow cytometry was used to determine the expression of Foxp3 and CTLA4 whereas cytokines secretion levels were measured by ELISA assay. Results. Tregs express both Axl and Mertk receptors. Gas6 increases the suppressive function of Tregs in vitro and in mice. Both Foxp3 and CTLA-4 expression on Tregs are enhanced after Gas6 stimulation. Gas6 enhances the suppressive activity of Tregs mainly through Axl receptor. Conclusion. Gas6 has a direct effect on the functions of CD4+CD25+Tregs mainly through its interaction with Axl receptor.

Gas6 expression is reduced in advanced breast cancers

“…In another study, dual inhibition of Gas6 and Mer decreased tumor-associated macrophages, increased CD4 + T cells and reduced tumor formation in lung cancer cells in vivo 46 . Gas6 has also been shown to enhance T regulatory cell (Treg) suppressor activity by binding Axl on Tregs 47 . In the present study, our data showed that stromal Gas6 expression did not significantly change during breast cancer progression (Supplemental Fig.…”

TAM-ing T cells in the tumor microenvironment: implications for TAM receptor targeting

“…We validated PROS1 signal transduction through MERTK using MERTK-inhibitors and knockdown of MERTK on CD8 + T cells [38]. As for GAS6, it has been reported that exogenous GAS6 could increase the suppressive properties of mouse CD4 + regulatory T cells via T cell-expressed AXL [41]. Furthermore, Keating et al overexpressed MERTK in mouse T lymphocytes [44].…”

“…The following year, Cabezon et al convincingly showed that TCR-activated human CD4 + T cells expressed MERTK from day 3 onwards [40]. In addition, it was reported that murine CD4 + regulatory T cells expressed both AXL and MERTK, without in vitro or in vivo stimulation [41]. Regarding CD3 + T cells, Yokoyama et al suggested that (mouse) CD45 + TILs could be responsible for increased MERTK levels in the tumormicroenvironment [42].…”

Large-scale Analyses of Disease Biomarkers and Apremilast Pharmacodynamic Effects

“…In psoriasis subjects, AXL, CA-15-3 and SP-D were significantly downregulated by apremilast. Of note, AXL and its upstream stimulus, IL-16 are known to be involved in Th1 16,17 , Treg 18 , and Th17 19 regulation. In psoriatic arthritis subjects, MPIF-1 (CCL23) was upregulated in the apremilast arm.…”