Interleukin-7 (IL-7) Treatment Accelerates Neutrophil Recruitment through γδ T-Cell IL-17 Production in a Murine Model of Sepsis

Abstract

The sepsis syndrome represents an improper immune response to infection and is associated with unacceptably high rates of mortality and morbidity. The interactions between T cells and the innate immune system while combating sepsis are poorly understood. In this report, we observed that treatment with the potent, antiapoptotic cytokine interleukin-7 (IL-7) accelerated neutrophil recruitment and improved bacterial clearance. We first determined that T cells were necessary for the previously observed IL-7-mediated enhanced survival. Next, IL-7 increased Bcl-2 expression in T cells isolated from septic mice as early as 3 h following treatment. This treatment resulted in increased gamma interferon (IFN-␥) and IP-10 production within the septic peritoneum together with local and systemic increases of IL-17 in IL-7-treated mice. We further demonstrate that the increase in IL-17 was largely due to increased recruitment and production by ␥␦ T cells, which express CXCR3. Consistent with increased IL-17 production, IL-7 treatment increased CXCL1/KC production, neutrophil recruitment, and bacterial clearance. Significantly, end-organ tissue injury was not significantly different between vehicle-and IL-7-treated mice. Collectively, these data illustrate that IL-7 can mediate the cross talk between Th1 and Th17 lymphocytes during sepsis such that neutrophil recruitment and bacterial clearance is improved while early tissue injury is not increased. All together, these observations may underlay novel potential therapeutic targets to improve the host immune response to sepsis.

Clinical review: Sepsis and septic shock - the potential of gene arrays

“…Recently, this paradigm was elegantly corroborated in mice subjected to sepsis and rescued by administration of IL-7, an anti-apoptotic cytokine essential for lymphocyte survival and expansion [44,45]. As mentioned previously, studies in human volunteers challenged with endotoxin revealed early repression of gene programs related to adaptive immunity [22].…”

Role of IL-17A in Neutrophil Recruitment and Hepatic Injury after Warm Ischemia–Reperfusion Mice

“…Recently, it was reported that gdT cells have been implicated as the major producer of IL-17 during sepsis (30). Furthermore, treatment of IL-7, which stabilizes the number of T cell and function, accelerates neutrophil recruitment through gd T cell IL-17 production in a murine model of sepsis (31). On the basis of these two reports, gd T cell could be involved in production of IL-17A in late phase after I/R.…”

Critical Illness–Induced Immune Suppression: Current State of the Science

“…Recombinant human IL-7 (rhIL-7) therapy has been evaluated in preclinical sepsis models, and data suggest benefi cial effects, including increased cytokine production capacity, T-cell proliferation, prevention of lymphocyte apoptosis, and improved survival. [65][66][67][68][69][70] Ex vivo treatment of lymphocytes from patients with sepsis with IL-7 signifi cantly improved T-cell proliferation, up-regulation of anti-apoptotic proteins, and IFN-γ production capacity. 63 Whereas rhIL-7 is currently being evaluated in patients with chronic viral infection and cancer, to date it remains unstudied in vivo in the setting of critical illness.…”