Cutting Edge: 2B4-Mediated Coinhibition of CD4+ T Cells Underlies Mortality in Experimental Sepsis

Abstract

Sepsis is a leading cause of death in the U.S. but the mechanisms underlying sepsis-induced immune dysregulation remain poorly understood. 2B4 (CD244, SLAM4) is a cosignaling molecule expressed predominantly on NK cells and memory CD8+ T cells that has been shown to regulate T cell function in models of viral infection and autoimmunity. Here we show that 2B4 signaling mediates sepsis lymphocyte dysfunction and mortality. 2B4 expression is increased on CD4+ T cells in both septic animals and human patients at early time points. Importantly, genetic loss or pharmacologic inhibition of 2B4 each significantly increased survival in a murine cecal ligation and puncture (CLP) model. Further, CD4-specific conditional knockouts showed that 2B4 functions on CD4+ T cell populations in a cell-intrinsic manner and modulates both adaptive and innate immune responses during sepsis. Our results illuminate a novel role for 2B4 coinhibitory signaling on CD4+ T cells in mediating immune dysregulation.

The gut microbiome alters immunophenotype and survival from sepsis

“…No differences were noted in bacteremia between septic Jax and CR mice despite differing survival and immunophenotype. This is a common finding in preclinical studies of sepsis (41). This potentially could be explained by induction of disease tolerance, in which the host protects against microbes by reducing the negative impact they have on host fitness (42).…”

Sepsis erodes CD8+ memory T cell-protective immunity against an EBV homolog in a 2B4-dependent manner

“…There is precedent for this as therapeutic blockade of PD‐1 and PD‐L1 has been tested in clinical trials to improve immune dysregulation following sepsis . Indeed, we recently showed that pharmacologic blockade of 2B4 reduced sepsis‐induced mortality in a model of CLP . Critical questions that will arise in considering therapeutic 2B4 blockade in septic patients include the timing of anti‐2B4 administration, because administration of a coinhibitory receptor blocker too early during the hyperinflammatory phase may exacerbate immune dysregulation and result in unwanted toxicities.…”

“…31,38,39 Additionally, previous work from our lab has uncovered a novel role for 2B4 coinhibitory signaling on CD4 + T cells in mediating immune dysregulation following sepsis. 40 Given these data and the clinical descriptions of significant rates of viral recrudescence following sepsis, we sought to interrogate the role of 2B4 in mediating the gHV-specific CD8 + T cells response in the setting of sepsis. We first assessed the frequency of 2B4 expression on antigen-experienced CD44 hi activated CD8 + T cells following sepsis, where a higher proportion of cells expressed 2B4 compared with the non-antigen-experienced CD44 lo population.…”

A novel role for coinhibitory receptors/checkpoint proteins in the immunopathology of sepsis

“…In studies looking at the role of CTLA-4 in sepsis-induced immunosuppression, blockade of CTLA-4 in conjunction with PD-1 also improved survival and reversed sepsis-induced immunosuppression as measured by reduced lymphocyte apoptosis in a sequential sepsis challenge model where CLP was followed by a secondary fungal insult (59). Recent studies by Chen et al (60) investigating the co-inhibitory molecule 2B4 indicate it may also markedly suppress CLP-induced complications. Together these results point to pathologically important roles for these co-inhibitory/checkpoint proteins and their signaling as underpinning the development of septic morbidity.…”

“…These changes include the restoration of the delayed type hypersensitivity response and a reduction of sepsis-induced CD4 + /CD8 + T as well as B lymphocyte cell death (47, 57, 61). In this regard, Chen et al (60) have recently reported that the expression of the co-inhibitory molecule 2B4 (CD244, SLAM4), which was initially reported to be upregulated on activated natural killer cells and CD8 + T cells (but not in experimental models of sepsis), is markedly upregulated on the splenic CD4 + T cells of not only CLP mice, but also on human patients with severe sepsis. Further, these CD4 + 2B4 + cells appear to upregulate PD-1 and CTLA-4, but inhibition of 2B4 activity is non-redundant to either PD-1 or CTLA-4.…”