Dataset Information

The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood ?? T cells.

ABSTRACT:

Background

B- and T-lymphocyte attenuator (BTLA) and programmed cell death-1 (PD-1) inhibit ?? 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 ?? T cells. Herein we demonstrate that the signalings of BTLA and PD-1 regulated proliferation and cytotoxicity of human ?? T cells, respectively.

Methods

Human peripheral blood ?? 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 ?? T cells.

Results

The proliferation of the ?? T cells was increased when PBMCs were cocultured with inactivated herpes virus entry mediator (HVEM)^low Jurkat cells. The cytotoxicity of the expanded ?? T cells was not affected by coculture with inactivated HVEM^low 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 ?? T cells without compromising ?? 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 ?? 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 ?? T cell proliferation and function and that the BTLA and PD-1 signaling pathways act independently on the proliferation and cytotoxicity of human peripheral ?? T cells.

SUBMITTER: Hwang HJ

PROVIDER: S-EPMC7860523 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The BTLA and PD-1 signaling pathways independently regulate the proliferation and cytotoxicity of human peripheral blood γδ T cells.

Hwang Hyun J HJ Lee Jae J JJ Kang Sung H SH Suh Jin K JK Choi Eun S ES Jang Seongsoo S Hwang Sang-Hyun SH Koh Kyung-Nam KN Im Ho J HJ Kim Nayoung N

Immunity, inflammation and disease 20201217 1

<h4>Background</h4>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.<h4>Methods</h4>Human peripheral blood γδ T cells were cultured with inactivated Jurkat ...[more]

PMID: 33332777

Similar Datasets

Project description:Acquired immune evasion is one of the mechanisms that contributes to the dismal prognosis of cancer. Recently, we observed that different γδ T cell subsets as well as CD8+ αβ T cells infiltrate the pancreatic tissue. Interestingly, the abundance of γδ T cells was reported to have a positive prognostic impact on survival of cancer patients. Since γδ T cells utilize TNF-related apoptosis inducing ligand (TRAIL) for killing of tumor cells in addition to granzyme B and perforin, we investigated the role of the TRAIL-/TRAIL-R system in γδ T cell-cytotoxicity toward pancreatic ductal adenocarcinoma (PDAC) and other cancer cells. Coculture of the different cancer cells with γδ T cells resulted in a moderate lysis of tumor cells. The lysis of PDAC Colo357 cells was independent of TRAIL as it was not inhibited by the addition of neutralizing anti-TRAIL antibodies or TRAIL-R2-Fc fusion protein. In accordance, knockdown (KD) of death receptors TRAIL-R1 or TRAIL-R2 in Colo357 cells had no effect on γδ T cell-mediated cytotoxicity. However, KD of decoy receptor TRAIL-R4, which robustly enhanced TRAIL-induced apoptosis, interestingly, almost completely abolished the γδ T cell-mediated lysis of these tumor cells. This effect was associated with a reduced secretion of granzyme B by γδ T cells and enhanced PGE2 production as a result of increased expression level of synthetase cyclooxygenase (COX)-2 by TRAIL-R4-KD cells. In contrast, knockin of TRAIL-R4 decreased COX-2 expression. Importantly, reduced release of granzyme B by γδ T cells cocultured with TRAIL-R4-KD cells was partially reverted by bispecific antibody [HER2xCD3] and led in consequence to enhanced lysis of tumor cells. Likewise, inhibition of COX-1 and/or COX-2 partially enhanced γδ T cell-mediated lysis of TRAIL-R4-KD cells. The combination of bispecific antibody and COX-inhibitor completely restored the lysis of TRAIL-R4-KD cells by γδ T cells. In conclusion, we uncovered an unexpected novel role of TRAIL-R4 in tumor cells. In contrast to its known pro-tumoral, anti-apoptotic function, TRAIL-R4 augments the anti-tumoral cytotoxic activity of γδ T cells.