Our analysis has revealed significant insights into immunology, illuminating the complex relationship between immune cells and sepsis risk. Specifically, we identified CD66b + + myeloid cells, BAFF-R on IgD- CD38br B cells, and CD39 on CD39 + CD8br regulatory T cells as crucial elements protecting against sepsis.
Our findings reveal a causal link between increased levels of CD66b + + myeloid cells and a lowered risk of sepsis. Traditionally, CD66b has been recognized as a neutrophil marker, highlighting cells known for their distinct nuclear shapes and short lifespans. The activation and clustering of these neutrophils, particularly under inflammatory conditions, have been closely associated with CD66b expression[31–33]. The relevance of CD66b + myeloid cells in sepsis has been underscored by numerous studies, which have explored their presence and pivotal roles in immune regulation and disease progression. In patients with sepsis, diverse subgroups of CD66b + CD10– myeloid cells, comprising varied cell types, have been identified[34]. Additionally, the presence of CD66b on immature CD33 + myeloid cells has been linked to immunosuppression driven by tumors[35]. Notably, the emergence of specific neutrophil subsets from the bone marrow in the context of COVID-19 shares similarities with sepsis, influencing immune responses[36]. Myeloid cell dysfunctions have been pinpointed as critical factors in the immunodeficiency triggered by sepsis, underlining the importance of further investigation[37–39]. Delving into these cells' molecular dynamics and roles is essential for devising precise therapeutic approaches and enhancing patient care.
Additionally, our research has highlighted the protective role of BAFF-R on IgD- CD38br B cells against sepsis. BAFF-R, the B-cell activating factor (BAFF) receptor, plays a pivotal role in B-cell biology, influencing survival, maturation, and homeostasis[40–46]. This receptor, primarily found on B-cells, is crucial for their survival and differentiation, with BAFF-R's presence necessary for developing and maintaining a healthy B-cell population[41, 42, 44]. Experiments with BAFF-R mutant mice have shown significant reductions in B-cell populations, indicating BAFF-R's essential role in primary B-cell survival and differentiation[41]. Additionally, BAFF-R acts as the primary receptor for BAFF costimulation in circulating T and B cells, underscoring its role in mediating immune responses[42]. It also serves as a vital conduit for BAFF-dependent B-cell signaling, which is critical for the late-stage maturation and survival of B-cells[43]. Disruption of BAFF/BAFF-R interactions has been observed to selectively deplete specific B-cell subsets, thereby attenuating disease activity in autoimmune diseases such as systemic lupus erythematosus[47]. The function of BAFF-R extends to the survival and upkeep of mature B cells, reinforcing its importance in sustaining immune health[45]. Given its extensive influence on B-cell development, survival, and participation in immune responses, BAFF-R's dysregulation is linked to autoimmune disorders and complications post-transplantation, emphasizing the need to thoroughly understand its role in immune system dynamics.
Our study underscores the protective influence of CD39 on CD39 + CD8br regulatory T cells (Tregs) against sepsis. CD39, known scientifically as ENTPD1, is integral to the operation of Tregs across numerous disease scenarios, including sepsis, where its expression on Tregs is linked to their immunosuppressive function and the modulation of immune stability[48]. Research has demonstrated that CD39 + Tregs can dampen cytokine production by specific CD8 T cells[49], showcasing their regulatory capabilities. In autoimmune hepatitis, the malfunction of CD39 + Tregs correlates with inadequate suppression of target cell proliferation, highlighting their role in immune moderation[50]. Additionally, the presence of CD39 on Tregs aligns with the suppression of tumor-infiltrating CD8 + T regulatory lymphocytes[51], emphasizing its significance in cancer immunology. In multiple sclerosis, CD39 + Tregs have been found to mitigate Th1 and Th17 responses to adenosine independently [52], illustrating their broad immunoregulatory functions. The imbalance observed between Th17 cells and Tregs expressing CD39 and CD73 in allergic asthma[53] points to the complex interactions in allergic diseases. Furthermore, CD39 expression on Tregs has been explored in specific conditions such as sarcoidosis, where it is associated with the induction of Foxp3-positive Tregs in granulomas[54], and in rheumatoid arthritis, where CD39 + Treg levels may serve as a biomarker for methotrexate treatment efficacy[55]. These findings affirm the pivotal role of CD39 expression on Tregs in modulating immune responses and preserving immune homeostasis across various diseases, spotlighting its therapeutic potential.