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Sepsis is a life-threatening condition arising from a dysregulated host response to infection, characterized by a complex interplay between pro-inflammatory and anti-inflammatory immune mechanisms. B cells, that are key components of humoral immunity, are essential for antibody production, antigen presentation, and immune modulation. Sepsis is commonly associated with B cell lymphopenia, particularly in severe cases, as evidenced by a marked reduction in circulating B cells in both adult and pediatric patients. However, the mechanisms driving this depletion have not been completely understood, particularly in pediatric sepsis. In this study, we employed single-cell RNA sequencing (scRNA-seq) to profile peripheral blood leukocytes from pediatric patients with sepsis (three with mild and three with severe condition) alongside four healthy controls. Our analysis revealed a broad depletion of immune cells in sepsis, with B cells showing the most pronounced reduction and the strongest capacity to discriminate between mild and severe disease states. Subset-level analysis identified significant loss and transcriptional reprogramming of natural killer-like B cells (ΝΚΒ), MHC IInaïve, and MHC IInaïve B cells in severe sepsis, accompanied by signatures indicative of intrinsic and extrinsic apoptosis, disrupted differentiation, and enhanced migratory potential. Importantly, we identified and validated the population of NKB cells in both pediatric and adult cohorts, broadening the known landscape of B cell phenotypes in human sepsis. We also explored intercellular communications, focusing on B cell-neutrophil interactions, given the notable neutrophilia observed, revealing potential crosstalk that may contribute to the overall immune dysregulation in sepsis. Collectively, these findings offer new insights into the cellular and molecular drivers of immune dysfunction in pediatric sepsis, shedding light on B cell depletion as a central feature of disease severity. This work lays the foundation for future diagnostic and therapeutic strategies targeting B cell-mediated immunity in septic children. The study was registered on ClinicalTrials.gov (NCT04103268), with registration date on 2019-09-23, before the first patient was enrolled.