Sepsis is a dysregulated systemic response to infection involving many inflammatory pathways and the induction of counter-regulatory anti-inflammatory processes that results in a state of immune incompetence and can lead to multi-organ failure. CXCR4 is a chemokine receptor that, following ligation by CXCL12, directs cells to bone marrow niches and also plays an important role in T cell cosignaling and formation of the immunological synapse. Here, we investigated the expression and function of CXCR4 in a murine model of polymicrobial sepsis. Results indicate that CXCR4 is selectively upregulated on naïve CD4+ and CD8+ T cells and CD4+ central memory T cells following the induction of sepsis, and that CXCR4 antagonism resulted in a significant decrease in sepsis-induced mortality. We probed the mechanistic basis for these findings and found that CXCR4 antagonism significantly increased the number of peripheral CD4+ and CD8+ T cells following sepsis. Moreover, mice treated with the CXCR4 antagonist contained fewer PD-1+ LAG-3+ 2B4+ cells, suggesting that blockade of CXCR4 mitigates CD4+ T cell exhaustion during sepsis. Taken together, these results characterize CXCR4 as an important pathway that modulates immune dysfunction and mortality following sepsis, which may hold promise as a target for future therapeutic intervention in septic patients.

CD8 T cell loss and dysfunction have been implicated in the increased susceptibility to opportunistic infections during the later immunosuppressive phase of sepsis, but CD8 T cell activation and attrition in early sepsis remain incompletely understood. With the use of a CLP model, we assessed CD8 T cell activation at 5 consecutive time points and found that activation after sepsis results in a distinct phenotype (CD69CD25CD62L) independent of cognate antigen recognition and TCR engagement and likely through bystander-mediated cytokine effects. Additionally, we observed that sepsis concurrently results in the preferential depletion of a subset of memory-phenotype CD8 T cells that remain "unactivated" (i.e., fail to up-regulate activation markers) by apoptosis. Unactivated CD44 OT-I cells were spared from sepsis-induced attrition, as were memory-phenotype CD8 T cells of mice treated with anti-LFA-1 mAb, 1 h after CLP. Perhaps most importantly, we demonstrate that attrition of memory phenotype cells may have a pathologic significance, as elevated IL-6 levels were associated with decreased numbers of memory-phenotype CD8 T cells in septic mice, and preservation of this subset after administration of anti-LFA-1 mAb conferred improved survival at 7 d. Taken together, these data identify potentially modifiable responses of memory-phenotype CD8 T cells in early sepsis and may be particularly important in the application of immunomodulatory therapies in sepsis.

Postoperative acute renal failure is a major cause of morbidity and mortality in colon and rectal surgery. Our objective was to identify preoperative risk factors that predispose patients to postoperative renal failure and renal insufficiency, and subsequently develop a risk calculator. Using the National Surgical Quality Improvement Program Participant Use Files database, all patients who underwent colorectal surgery in 2009 were selected (n = 21,720). We identified renal complications during the 30-day period after surgery. Using multivariate logistic regression analysis, a predictive model was developed. The overall incidence of renal complications among colorectal surgery patients was 1.6 per cent. Significant predictors include male gender (adjusted odds ratio [OR]: 1.8), dependent functional status (OR: 1.5), preoperative dyspnea (OR: 1.5), hypertension (OR: 1.6), preoperative acute renal failure (OR: 2.0), American Society of Anesthesiologists class ≥3 (OR: 2.2), preoperative creatinine >1.2 mg/dL (OR: 2.8), albumin <3.5 g/dL (OR: 1.8), and emergency operation (OR: 1.5). This final model has an area under the curve (AUC) of 0.79 and was validated with similar excellent discrimination (area under the curve: 0.76). Using this model, a risk calculator was developed with excellent predictive ability for postoperative renal complications in colorectal patients and can be used to aid clinical decision-making, patient counseling, and further research on measures to improve patient care.

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