The BTLA and PD‐1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells
Hyun Ju Hwang, Jae J. Lee, Sung Han Kang, Jin Kyung Suh, Eun Seok Choi, Seongsoo Jang, Sang‐Hyun Hwang, Kyung‐Nam Koh, Ho Joon Im, Nayoung Kim
Abstract
BACKGROUND: B- and T-lymphocyte attenuator (BTLA) and programmed cell death-1 (PD-1) inhibit γδ T cell homeostasis and activation. This study aimed to determine whether BTLA and PD-1 signaling pathways were convergent or independent in human peripheral blood γδ T cells. Herein we demonstrate that the signalings of BTLA and PD-1 regulated proliferation and cytotoxicity of human γδ T cells, respectively. METHODS: Human peripheral blood γδ T cells were cultured with inactivated Jurkat cells in the presence of interleukin-2 and zoledronate (Zol) for 14 days. Flow cytometry was performed to evaluate the phenotypes and functions of γδ T cells. RESULTS: Jurkat cells and was further increased in the presence of anti-PD-L1 mAb. These results suggest that the inactivation of the BTLA signaling pathway during expansion could help produce more γδ T cells without compromising γδ T cell function. The inhibition of BTLA or PD-1 signaling repressed phosphorylation of the src homology region 2-containing protein tyrosine phosphatase 2 and increased the phosphorylation of protein kinase B in γδ T cells. However, there were no synergistic or additive effects by a combination of BTLA and PD-1 blockade. CONCLUSION: These results suggest that BTLA signaling is crucial in regulating γδ T cell proliferation and function and that the BTLA and PD-1 signaling pathways act independently on the proliferation and cytotoxicity of human peripheral γδ T cells.