Systemic immune dysregulation leading to immune suppression is increasingly being recognized as a major contributor to sepsis-induced mortality. However, the mechanisms underlying this immune suppression are incompletely understood. Landmark studies in models of chronic viral infection have revealed that coinhibitory molecules each play distinct and non-redundant roles in inducing T cell exhaustion, suggesting that the constellation of distinct coinhibitory molecules expressed on the surface of T cells during the execution of an immune response correlate to different stages and degrees of T cell function and/or exhaustion. Thus, we sought to determine whether other novel coinhibitory molecules participate in the immunosuppressive phase that may increase the risk of mortality during sepsis. 284 (CD244, SLAMf4) is a 3SkD type I transmembrane protein and member of the CD2 subset of the immunoglobulin superfamily that is best known for its role on NK cells but has more recently been appreciated as a coinhibitory receptor on subsets of CD4+ and CDS+ T cells. In order to determine the role of 284 during sepsis, we induced cecal ligation and puncture (CLP) in wild-type 86 animals or those that were genetically deficient in 284. Strikingly, while wild-type animals exhibited S2% mortality following CLP, only 13% of 284_,_ animals died. Thus, the absence of 284 rendered animals 6 times less likely to die during sepsis. Preliminary data also suggests that 284 modifies immune dysregulation during sepsis, and analysis of human T cells during acute septic injury revealed an increase in the expression of 284 on both CD4+ and CDS+ T cells, in particular on memory T cell subsets. Thus, in this proposal we aim to determine how 284 contributes to sepsis-induced mortality, the cell type(s) by which it mediates its effects, and when during sepsis 284 contributes to sepsis-induced mortality. This proposal is innovative in that our preliminary data reveal that 284 is highly expressed in humans and mice on memory CD4+and CDS+ T cells. However, standard laboratory mice contain only a very small percentage of memory T cells (2-5%), owing to their SPF housing conditions. Thus, in this grant, we also propose a novel approach to study sepsis pathogenesis: to utilize mice that have been previously infected with several acutely cleared pathogens in order to generate memory mice; that is, mice that contain memory T cells at a frequency similar to that observed in adult humans (30-50%). We will dissect the role of 284 expressed on memory CD4+ and CDS+ T cells in sepsis-induced immune dysregulation and mortality, and determine the impact of 284 induced during sepsis on antigen-specific memory T cell responses to both a bacterial and a latent viral second hit. Interrogation of the mechanisms by which inhibition of 284-mediated coinhibitory signals protects mice from death during sepsis is critical for the potential future translation of immunomodulatory strategies to target this pathway to prevent death in septic patients. B.
As the third most common cause of death in the United States following heart disease and cancer, sepsis represents a prevalent and deadly public health issue, but alarmingly, there are no approved therapeutics available for sepsis once antibiotics and supportive therapy fail. We discovered that expression of a molecule expressed on lymphocytes, termed 2B4, is increased during sepsis, and our studies of sepsis in a mouse model revealed that while WT animals exhibited 82% mortality following CLP, only 13% of 2B4-deficient animals died. In this grant we propose to determine the mechanisms by which 2B4 contributes to sepsis induced mortality, and to extend our murine findings to human septic patients by assessing the upregulation of 2B4 on human immune cells during sepsis, because investigation of the mechanisms by which inhibition of the 2B4 pathway protects mice from death during sepsis is critical for potential future strategies to target this pathway to prevent death in septic patients.
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|Zingarelli, Basilia; Coopersmith, Craig M; Drechsler, Susanne et al. (2018) Part I: Minimum Quality Threshold in Pre-Clinical Sepsis Studies (MQTiPSS) for Study Design And Humane Modeling Endpoints. Shock :|
|Fay, Katherine T; Chihade, Deena B; Chen, Ching-Wen et al. (2018) Increased mortality in CD43-deficient mice during sepsis. PLoS One 13:e0202656|
|Xie, Jianfeng; Robertson, Jennifer M; Chen, Ching-Wen et al. (2018) Pre-existing malignancy results in increased prevalence of distinct populations of CD4+ T cells during sepsis. PLoS One 13:e0191065|
|Breed, Elise R; Hilliard, Carolyn A; Yoseph, Benyam et al. (2018) The small heat shock protein HSPB1 protects mice from sepsis. Sci Rep 8:12493|
|Lyons, John D; Chen, Ching-Wen; Liang, Zhe et al. (2018) Murine Pancreatic Cancer Alters T Cell Activation and Apoptosis and Worsens Survival After Cecal Ligation and Puncture. Shock :|
|Klingensmith, Nathan J; Fay, Katherine T; Lyons, John D et al. (2018) Chronic Alcohol Ingestion Worsens Survival and Alters Gut Epithelial Apoptosis and Cd8+ T Cell Function after Pseudomonas Aeruginosa Pneumonia-Induced Sepsis. Shock :|
|Laurie, Sonia J; Liu, Danya; Wagener, Maylene E et al. (2018) 2B4 Mediates Inhibition of CD8+ T Cell Responses via Attenuation of Glycolysis and Cell Division. J Immunol 201:1536-1548|
|Lorentz, C Adam; Liang, Zhe; Meng, Mei et al. (2017) Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis. Mol Med 23:155-165|
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