Divergent invariant natural killer T-cell response to sepsis of abdominal vs. non-abdominal origin in human beings.

BACKGROUND: The etiology of sepsis is broad. The peritoneal cavity displays compartmentalization with respect to inflammatory responses, so peripheral blood responses to sepsis of abdominal vs. non-abdominal origin are expected to be divergent. Lymphocytes and invariant natural killer T (iNKT) cells play important roles in survival from sepsis, as they dampen the neutrophil and macrophage responses. We assessed whether circulating iNKT cells display distinct phenotypic profiles depending on the presence of abdominal vs. non-abdominal infection with sepsis. METHODS: Patients with sepsis, defined as infection confirmed microbiologically with a systemic inflammatory response syndrome (SIRS), were enrolled prospectively. They were categorized as having either exclusively sepsis of abdominal or exclusively non-abdominal origin. The white blood cell (WBC) count was recorded. Whole-blood staining with monoclonal antibodies to CD3, V-alpha-24 (to identify iNKT cells), and CD69 (marker of early activation) was applied. RESULTS: Of the 53 enrolled patients, 18 had abdominal infection. Pneumonia was the most common non-abdominal type. There was no difference in gender, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, WBC count, or CD3(+) T cells (7.1%±1.6% vs. 6.5%±0.9%; p=0.75) in the two groups. Patients with abdominal infection had a higher proportion of iNKT cells (2.7%±1.1% vs. 0.89%±0.14%; p=0.032). Correcting for WBC count, this translated into a higher absolute number of iNKT cells (3.4±1.8×10(7)/L vs. 0.74±0.15×10(7)/L; p=0.03). Patients with sepsis of abdominal origin had a lower percentage of CD69(+) iNKT cells (9.1%±3.1% vs. 27.2%±5.8%; p=0.028). In patients in shock vs. those who were not, patients with non-abdominal infection exhibited a greater number of iNKT cells (1.47±0.3 v. 0.62±0.1×10(7)/L; p=0.022) and percentage of activated iNKT cells (53±14.5% vs. 17.9±4.8%; p=0.04). Patients with non-abdominal infection who died had a lower absolute number of activated iNKT cells (0.8±1.2×10(7)/L vs. 0.34±0.1×10(7)/L; p=0.023); however, no such shock or death correlation was noted in patients with sepsis of abdominal origin. CONCLUSIONS: Divergent sepsis etiologies display distinct blood iNKT cell population changes. In non-abdominal infection, this difference was associated with septic shock and death. Elucidating the importance and basis for these changes relative to the response to sources of infection will help clarify appropriate diagnosis and management of the patient with sepsis.

BTLA expression contributes to septic morbidity and mortality by inducing innate inflammatory cell dysfunction.

A proper innate inflammatory response is essential for prevention of the systemic inflammation associated with sepsis. BTLA is an immune-regulatory receptor demonstrated to be expressed not only on adaptive immune populations and have potent inhibitory effects on CD4(+) T cells but is also expressed on innate cell populations (CD11c(+) and CD11b(+) cells) and has been shown to diminish pathogen clearance following bacterial and parasite infection. The role of BTLA in sepsis and the mechanisms by which BTLA alters pathogen clearance, however, have not been addressed clearly. Here, we show that following acute experimental sepsis induction in mice (CLP), the number of infiltrating BTLA- and HVEM (the ligand for BTLA)-expressing macrophages, inflammatory monocytes, mature and immature DCs, and neutrophils increased in the peritoneum compared with sham surgery, suggesting that a high level of HVEM:BTLA interactions occurs between these cells at the site of septic insult. Given this, we evaluated BTLA(-/-) mice, 24 h post-CLP, and observed a marked increase in the degree of activation on these cell populations, as well as a reduction in peritoneal bacterial burden and IL-10 induction, and most importantly, BTLA(-/-) mice exhibited a higher rate of survival and protection from organ injury when compared with WT mice. Such changes were not restricted to experimental mice, as circulating BTLA+ and HVEM+ monocytes and HVEM+ granulocytes were increased in septic ICU patients, supporting a role for BTLA and/or HVEM as potential, novel diagnostic markers of innate immune response/status and as therapeutic targets of sepsis.