Sepsis 3.0 is defined as a dangerous organ malfunction elicited by an unregulated host reaction to infectious agents [1]. In 2017, there were around 48.9 million cases of sepsis worldwide, which caused the deaths of 11 million people [2]. Remarkably, this figure signifies an alarming 19.7 % of all global fatalities. According to the Centers for Disease Control and Prevention (CDC), sepsis affects over 1.7 million adults annually in the US, leading to about 350,000 deaths in hospitals or after transitioning to palliative care (CDC, 2020). In 2022, a study on sepsis in the ICU involving 22,748 patients revealed that the incidence and mortality rates of sepsis in Chinese ICU wards were 25.5 % and 40 %, respectively [3].

These findings highlight the critical need for early sepsis detection and prompt therapeutic intervention. The early stages of sepsis are crucial for intervention, given their significant clinical and immunological impacts. During sepsis's early phase, immune responses must navigate a fine line between pathogen clearance and the risk of rampant inflammation [4], [5]. Early immunomodulatory intervention can alter the disease's course, reducing the risk of severe outcomes. Therefore, understanding early-stage immune activation is critical for developing therapies to prevent progression to severe sepsis or septic shock by effectively modulating the immune response [5].

Under conditions of infection, the interaction between CD4+ T cells and innate immune cells is crucial for the initiation and amplification of the host's defense mechanisms. CD4+ T cells, through the secretion of IFN-γ, are capable of activating macrophages and NK cells, enhancing their phagocytic and bactericidal activities. Conversely, macrophages promote the activation and differentiation of CD4+ T cells by presenting antigens and providing costimulatory signals. Moreover, dendritic cells, serving as the principal antigen-presenting cells, specialize in capturing and processing antigens to present them to CD4+ T cells, thereby strengthening the activation of specific immunity [6]. In the realm of adaptive immunity, the interaction between CD4+ T cells and B cells facilitates the differentiation of B cells into antibody-producing plasma cells and aids in the formation of long-term immune memory [7]. Concurrently, CD4+ T cells support the proliferation and differentiation of CD8+ T cells into cytotoxic effector T cells capable of pathogen clearance by producing cytokines like IL-2. Furthermore, CD4+ T cells are modulated by specific cytokines to differentiate into various T cell subsets, such as Th1, Th2, Th17, or regulatory T cells, ensuring that the immune response to different pathogens is appropriately regulated and optimized [8]. Understanding the early immune response in sepsis, where innate and adaptive immunity intertwine, is crucial for guiding treatment strategies and enhancing patient outcomes [5], [9].

While significant research has highlighted the prompt response of innate immune cells like neutrophils and the monocyte-macrophage system in sepsis, the role of CD4+ T helper (Th) cells in bridging innate and adaptive immunity deserves attention. Upon activation, these cells quickly increase interferon and interleukin levels, thereby aiding innate immune cells in pathogen elimination and stimulating B cells to produce specific antibodies. Yet, research into the mechanisms that regulate adaptive immune activation at the onset of sepsis is in its infancy. Although the adaptive immune response’s specificity might not fully develop in the early sepsis stages, CD4+ T cells' early activation is pivotal, setting the stage for a more targeted immune response [10]. Immune dysfunction at this stage can lead to either weakened or excessive inflammatory responses, significantly impacting sepsis prognosis early on.

EFHD2, also known as Swiprosin-1, is a calcium-binding cytoskeletal protein that is expressed in a variety of cells including B cells, CD4+/CD8+ T cells, natural killer cells, and macrophages. It plays a critical role in the immune system and has been implicated in numerous cellular functions such as the formation of actin filaments, cytoskeletal regulation, cell apoptosis and migration, and cell signaling pathways [11], [12]. Previous studies by our research group have demonstrated that EFHD2 regulates macrophage recruitment induced by LPS through enhancing actin polymerization and cell migration [13]. The upregulation and tyrosine phosphorylation of EFHD2 during LPS stimulation highlight its role in the mobilization of immune cells and the inflammatory response [13], [14]. Additionally, EFHD2 interacts with phosphorylated IFN-γR2 during intracellular bacterial infections, promoting the translocation of IFN-γR2 from the Golgi apparatus to the plasma membrane of macrophages, thereby facilitating IFN-γ signaling in subsequent innate responses [15]. EFHD2 also plays a regulatory role in the adaptive immune system. Initial studies on how EFHD2 enhances B cell receptor (BCR) signaling and promotes apoptosis induced by BCR, underscore its crucial function in regulating the lifespan of immature B cells and the BCR signaling threshold [16]. It has been shown that EFHD2 controls BCR signaling by organizing BCR, Syk, and PLC-γ2 in membrane lipid rafts, highlighting its significance in BCR signal transduction [17]. Research on CD8+ T cells has identified EFHD2′s crucial role in stabilizing the immune synapse [18]. Together, these studies paint a comprehensive picture of EFHD2′s multifaceted roles in both innate and adaptive immunity, offering valuable insights into the biological functions of EFHD2.

Research on EFHD2′s role in T cells, especially CD4+ T cells, is scarce. Considering CD4+ T cells' pivotal role in adaptive immunity, investigating EFHD2′s functions and effects is valuable. This study examines EFHD2′s influence on CD4+ T cell activation during early sepsis, finding it essential for initial T cell activation. This suggests EFHD2 as an early sepsis intervention target. Our aim is to enhance understanding of sepsis immunotherapy by revealing EFHD2′s novel role in T cell immunity. We investigated EFHD2 expression in CD4+ T cells using early sepsis animal models and patient data analysis. Further exploring the mechanism, we analyzed human and Efhd2 knockout mice RNA transcriptomes. This revealed significant impacts on processes related to T cell receptor (TCR) activation, leading to phenotype validation experiments to confirm bioinformatics findings. Using immunofluorescence confocal microscopy and protein-level analysis of downstream signaling pathways, we verified EFHD2′s role in TCR signaling activation. Overall, our findings enrich the comprehension of EFHD2′s role in adaptive immunity.