Objective: Although T-cell-mediated inflammation is a hallmark of Type 2 Diabetes (T2D), the contribution of CD20-expressing T cells—a highly potent subset recently implicated in various autoimmune conditions—to T2D pathogenesis remains unknown. This study aimed to characterize the frequency, functional profile, and glucose-responsiveness of CD20+ cytotoxic T lymphocytes (CTLs) in patients with T2D. Research Design and Methods: Peripheral blood mononuclear cells (PBMCs) from 25 treatment-naïve T2D patients and 20 age-matched healthy controls (HC) were analyzed using multicolor flow cytometry. We assessed the frequency of CD3+CD8+CD20+ cells and their production of cytotoxic molecules (Granzyme B, Perforin, Granzyme K) and pro-inflammatory cytokines (IFN-γ, TNF-α, GM-CSF). To further establish the link with hyperglycemia, HC-derived CTLs were exposed to increasing glucose concentrations (100–450 mg/dL) in vitro. Single-cell RNA sequencing (scRNA-seq) data from a public T2D dataset was utilized to validate the molecular signature of MS4A1 (CD20)+ CTLs. Results: The frequency of circulating CD20+ CTLs was significantly elevated in T2D patients compared to HCs (p<0.0001) and demonstrated a strong positive correlation with HbA1c, fasting glucose, and triglyceride levels. Notably, CD20+ CTLs from T2D patients exhibited a “hyperfunctional” phenotype, characterized by significantly higher degranulation (CD107a), elevated expression of Granzymes B/K and Perforin, and increased production of IFN-γ and TNF-α compared to HCs (p<0.01 for all). In contrast, no such differences were observed in the CD20-CTL compartment. In vitro experiments revealed that escalating glucose levels directly enhanced the proliferation and cytotoxic potential of CD20+ CTLs, suggesting a nutrient-sensing mechanism. scRNA-seq analysis further confirmed the distinct pro-inflammatory and effector transcriptional profile of MS4A1+ T cells in T2D. Conclusions: Our findings identify CD20+ CTLs as a novel, glucose-sensitive, and hyperfunctional immune subset in T2D. The strong correlation between these cells and clinical metabolic parameters suggests that CD20+ CTLs may act as a critical link between chronic hyperglycemia and systemic inflammation, representing a potential new therapeutic target for immunomodulation in T2D.

Aim: Antibiotic de-escalation (ADE) is essential, but appears to be underperformed although being possible, which we refer to as a ‘missed opportunity’. We aimed to analyze the ADE missed opportunities in Gram-negative bloodstream infections (BSIs) in a setting with a high antimicrobial resistance profile. Methods: A retrospective, two-centered cohort study was performed from 1 January 2018 to 30 June 2019, including adults with mono- or polymicrobial Gram-negative BSIs. All ADE episodes and 30-day mortality were noted. Results/Discussion: Out of 273 BSIs (43 ADE vs. 230 no-ADE episodes), 101 were considered a ‘missed’ opportunity of ADE (36.9%, 101/273). In multivariate analysis, ADE opportunities were missed 4.4 times more (OR = 4.4; 95% CI 1.24–15.9) in the presence of hematological malignancy and 6.2 times more (OR = 6.2; 95% CI 1.76–22.2) in ESBL. Contrary to this, ADE opportunities were missed 0.24 times less (OR = 0.24; 95% CI 0.09–0.61) among patients with E. coli BSIs, and 0.17 less (OR = 0.17; 95% CI 0.05–0.67) if ertapenem was used as an empirical agent. The ADE missed opportunity group had a higher mortality rate, which is statistically significant in univariate analysis, but not in multivariate analysis. Conclusion: The presence of ESBL and hematological malignancy were the significant barriers to appropriate ADE practice in our study. A good stewardship program must address physician hesitation in ADE practice.