Recipient NK cell inactivation and intestinal barrier loss are required for MHC-matched graft-versus-host disease

Abstract

Previous studies have shown a correlation between pre-transplant conditioning intensity, intestinal barrier loss, and graft-versus-host disease (GVHD) severity. However, since irradiation and other forms of pre-transplant conditioning have pleiotropic effects, the precise role of intestinal barrier loss in GVHD pathogenesis remains unclear. We developed GVHD models that allowed us to isolate the specific contributions of distinct pre-transplant variables. First, intestinal damage was required for the induction of minor mismatch (MHC-matched) GVHD, but was not necessary for major mismatch GVHD, demonstrating fundamental pathogenic distinctions between these forms of disease. Moreover, recipient NK cells prevented minor mismatch GVHD by limiting expansion and target organ infiltration of alloreactive T cells via a perforin-dependent mechanism, revealing a previously unrecognized immunoregulatory function of recipient NK cells in GVHD. Minor mismatch GVHD required MyD88-mediated TLR4 signaling on donor cells, and intestinal damage could be bypassed by parenteral LPS administration, indicating a critical role for the influx of bacterial components triggered by intestinal barrier loss. In all, the data demonstrate that pre-transplant conditioning plays a dual role in promoting minor mismatch GVHD by both depleting recipient NK cells and inducing intestinal barrier loss.

The mucosal barrier at a glance

“…GVHD is a complication that can occur following a bone marrow or hematopoietic stem cell transplant, whereby the recipient's body cells are attacked by donor-derived immune cells. Using a clinically relevant mouse model of GVHD, epithelial damage has been determined to be essential for disease pathogenesis (Nalle et al, 2014). Consistent with the crucial role of the intestinal barrier in limiting GVHD, the requirement for epithelial injury could be circumvented through intraperitoneal administration of bacterial lipopolysaccharides -i.e.…”

“…Consistent with the crucial role of the intestinal barrier in limiting GVHD, the requirement for epithelial injury could be circumvented through intraperitoneal administration of bacterial lipopolysaccharides -i.e. endotoxin (Nalle et al, 2014).…”

Mechanisms of Intestinal Barrier Dysfunction in Sepsis

“…Although the intestinal tract is lined with only a single layer of epithelial cells, it acts as a selective barrier allowing paracellular movement of water, solutes and immune modulating factors while preventing the diffusion of potentially harmful pathogens, toxins, and antigens from the luminal environment into the circulation and mesenteric lymph (8–10). Selective permeability is maintained in large part via the apical tight junction containing numerous claudin isoforms, occludin and ZO-1.…”

Myosin Light Chain Kinase Knockout Improves Gut Barrier Function and Confers a Survival Advantage in Polymicrobial Sepsis

“…While early studies in critical illness hypothesized that gut barrier damage induces sepsis by translocation of intact bacteria, the reality has turned out to be considerably more complex (7,(22)(23)(24). The intestine acts as a selective barrier, preventing movement of potentially damaging microbes, toxins and antigens from the gut lumen, while simultaneously allowing paracellular movement of water, solutes and immune-modulating factors (25)(26)(27). Luminal contents can exit the internal environment of the gut into the local environment or the systemic circulation via the portal circulation or mesenteric lymph, where they can cause distant organ damage or alter inflammation.…”