The interaction of the tumor necrosis factor receptor (TNFR) family member CD27 on naive CD8+ T (Tn) cells with homotrimeric CD70 on antigen-presenting cells (APCs) is necessary for T cell memory fate determination. Here, we examined CD27 signaling during Tn cell activation and differentiation. In conjunction with T cell receptor (TCR) stimulation, ligation of CD27 by a synthetic trimeric CD70 ligand triggered CD27 internalization and degradation, suggesting active regulation of this signaling axis. Internalized CD27 recruited the signaling adaptor TRAF2 and the phosphatase SHP-1, thereby modulating TCR and CD28 signals. CD27-mediated modulation of TCR signals promoted transcription factor circuits that induced memory rather than effector associated gene programs, which are induced by CD28 costimulation. CD27-costimulated chimeric antigen receptor (CAR)-engineered T cells exhibited improved tumor control compared with CD28-costimulated CAR-T cells. Thus, CD27 signaling during Tn cell activation promotes memory properties with relevance to T cell immunotherapy.
Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

The adjuvanted varicella-zoster virus (VZV) glycoprotein E (gE) subunit herpes zoster vaccine (HZ/su) confers higher protection against HZ than the live attenuated zoster vaccine (ZV). To understand the immunologic basis for the different efficacies of the vaccines, we compared immune responses to the vaccines in adults 50 to 85 years old. gE-specific T cells were very low/undetectable before vaccination when analyzed by FluoroSpot and flow cytometry. Both ZV and HZ/su increased gE-specific responses, but at peak memory response (PMR) after vaccination (30 days after ZV or after the second dose of HZ/su), gE-specific CD4+ and CD8+ T cell responses were 10-fold or more higher in HZ/su compared with ZV recipients. Comparing the vaccines, T cell memory responses, including gE-IL-2+ and VZV-IL-2+ spot-forming cells (SFCs), were higher in HZ/su recipients and cytotoxic and effector responses were lower. At 1 year after vaccination, all gE-Th1 and VZV-IL-2+ SFCs remained higher in HZ/su compared with ZV recipients. Mediation analyses showed that IL-2+ PMR were necessary for the persistence of Th1 responses to either vaccine and VZV-IL-2+ PMR explained 73% of the total effect of HZ/su on persistence. This emphasizes the biological importance of the memory responses, which were clearly superior in HZ/su compared with ZV participants.

The T‑cell immunoglobulin and mucin domain‑containing protein 3 (Tim‑3)/galectin 9 (Gal‑9) pathway, which serves a pivotal role in immune regulation, is similar to the programmed death (PD)‑1/PD‑ligand 1 pathway. Recent evidence has suggested that Tim‑3 is differentially regulated in a variety of tumors and is a potential therapeutic target. The aim of the present study was to evaluate Tim‑3 and Gal‑9 expression and cluster of differentiation (CD)3+, CD8+ and forkhead box (FOX)p3+ T cell tumor‑infiltration in gastric cancer, as well as their impact on prognosis. Tissue samples from 587 patients with gastric cancer were used to create a tissue microarray (TMA). The immune markers Tim‑3, Gal‑9, CD3, CD8 and FOXp3 were immunostained in the TMA, and correlations with clinicopathological findings and prognosis were analyzed. Several Gene Expression Omnibus gastric cancer databases and the K‑M plotter website were used to analyze the association between the expression of Tim‑3, Gal‑9 and CD8A RNA and patient survival. The results demonstrated that Tim‑3 was mainly expressed in immune cells, with minimal expression in gastric cancer cells. Its ligand, Gal‑9, was significantly overexpressed in tumor cells. Tim‑3 and Gal‑9 expression and Foxp3+ T cell density were negatively associated with the patient overall survival (OS) rate. The density of CD8+ T cells was positively associated with the patient OS rate. Tim‑3 expression and CD8+ T cell density were revealed to be independent prognostic factors for patients with gastric cancer.