Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1.

T cell polyfunctionality is a hallmark of protective immunity against pathogens and cancer, yet the molecular mechanism governing it remains mostly elusive. We found that canonical Wnt agonists inhibited human memory CD8+ T cell differentiation while simultaneously promoting the generation of highly polyfunctional cells. Downstream effects of Wnt activation persisted after removal of the drug, and T cells remained polyfunctional following subsequent cell division, indicating the effect is epigenetically regulated. Wnt activation induced a gene expression pattern that is enriched with stem cell-specific gene signatures and upregulation of protein arginine methyltransferase 1 (PRMT1), a known epigenetic regulator. PRMT1+CD8+ T cells are associated with enhanced polyfunctionality, especially the ability to produce IL-2. In contrast, inhibition of PRMT1 ameliorated the effects of Wnt on polyfunctionality. Chromatin immunoprecipitation revealed that H4R3me2a, a permissive transcription marker mediated by PRMT1, increased at the IL-2 promoter loci following Wnt activation. In vivo, Wnt-treated T cells exhibited superior polyfunctionality and persistence. When applied to cytomegalovirus (CMV) donor-seropositive, recipient-seronegative patients (D+/R-) lung transplant patient samples, Wnt activation enhanced CMV-specific T cell polyfunctionality, which is important in controlling CMV diseases. These findings reveal a molecular mechanism governing T cell polyfunctionality and identify PRMT1 as a potential target for T cell immunotherapy.

Benefit of Three-dimensional Image Simulation in Surgical Resection of Early-stage Lung Cancer.

BACKGROUND: The present study investigated the oncologic outcomes of clinical stage IA2 non-small cell lung cancer (NSCLC) treated using preoperative simulation and surgical resection. METHODS: Data of patients who underwent surgical resection for clinical stage IA2 NSCLC between January 2002 and June 2018 were reviewed. Preoperative simulations were indicated for patients with centrally located tumors who could undergo anatomic resection. Clinical features, imaging characteristics of the tumors, surgical approaches, and outcomes were analyzed. RESULTS: Of the 1086 identified patients, 281 patients with clinical stage IA2 NSCLC were enrolled and categorized into 2 groups, with and without preoperative simulation. Tumor location, maximum standard uptake value, histologic grade, disease-free survival, and disease recurrence were significantly different between the 2 groups. For patients with preoperative simulations, 70.7% underwent anatomic resection, whereas for patients without preoperative simulations, 79.7% underwent anatomic resection (P < .001). Patients with preoperative simulations had fewer relapses (2%) than patients without preoperative simulations (11.5%, P < .01). CONCLUSIONS: Preoperative simulation confirmed the relationship between the tumor and surrounding blood vessels and bronchus and ensured an oncologic safety margin. Three-dimensional simulations are a useful and feasible tool for planar operative procedures and satisfy the requirements for early-stage NSCLC. These results are promising but preliminary, and more extended follow-up is needed.

Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4 + and CD8 + T-cell responses in older adults positively correlates with response size.

Cytomegalovirus (CMV) infection is one of the most common persistent viral infections in humans worldwide and is epidemiologically associated with many adverse health consequences during aging. Previous studies yielded conflicting results regarding whether large, CMV-specific T-cell expansions maintain their function during human aging. In the current study, we examined the in vitro CMV-pp65-reactive T-cell response by comprehensively studying five effector functions (i.e., interleukin-2, tumor necrosis factor-α, interferon-γ, perforin, and CD107a expression) in 76 seropositive individuals aged 70 years or older. Two data-driven, polyfunctionality panels (IL-2-associated and cytotoxicity-associated) derived from effector function co-expression patterns were used to analyze the results. We found that, CMV-pp65-reactive CD8 + and CD4 + T cells contained similar polyfunctional subsets, and the level of polyfunctionality was related to the size of antigen-specific response. In both CD8 + and CD4 + cells, polyfunctional cells with high cytotoxic potential accounted for a larger proportion of the total response as the total response size increased. Notably, a higher serum CMV-IgG level was positively associated with a larger T-cell response size and a higher level of cytotoxic polyfunctionality. These findings indicate that CMV-pp65-specific CD4 + and CD8 + T cell undergo simultaneous cytotoxic polyfunctionality maturation during aging.