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

Abstract

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.

B and T lymphocyte attenuator inhibits LPS-induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells

“…Sun et al (18) have shown that BTLA −/− mice exhibit significantly higher bacterial clearance compared with WT mice in the early phase of bacterial infection. Shubin et al (19) have also shown that BTLA −/− mice exhibited a higher rate of survival and protection from cecal ligation and puncture. Moreover, Adler et al (20) have shown that BTLA −/− mice exhibit strongly enhanced parasite clearance and that the increased clearance is seen before the onset of acquired immune responses.…”

“…Because BTLA −/− mice have been reported to exhibit significantly higher pathogen clearance compared with WT mice (18)(19)(20), the administration of 6A6 is of potential concern for the suppression of pathogen clearance. However, it has been reported that 6A6 does not perturb protective immunity against pathogens (16,24).…”

The immunopathology of sepsis and potential therapeutic targets

“…A phase Ib/IIa study testing a PDL1-specific antibody in patients with sepsis is under way, and secondary outcome measures in this trial include changes in biomarkers of immune suppression as readouts of the effects of treatment 126 . Other immune checkpoints that have been targeted in preclinical sepsis models and have been shown to improve survival include B and T lymphocyte attenuator (BTLA), and cytotoxic T lymphocyte-associated molecule 4 (CTLA4) 127,128 , but studies investigating the targeting of these checkpoints in human sepsis have not yet been performed.…”

Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye

“…During acute experimental sepsis, HVEM-BTLA interactions on innate populations worsen outcomes with respect to organ injury, bacterial burden, and mortality (106) HVEM and adaptive immune responses. Helper Th1 CD4 ϩ T cells are considered to represent the major immunopathologic cell type in HSK (9,10,15).…”