The Role of Epidermal Growth Factor in Mediating Survival in Mouse Sepsis is Dependent Upon an Intact Adaptive Immune System

Epidermal growth factor (EGF) has healing effects on the intestinal mucosa and improves survival when administered systemically after the onset of preclinical sepsis. The intestine plays a key role in this improvement in mortality as transgenic mice that overexpress EGF only in the villus epithelium also have a survival benefit. However, EGF also has extraintestinal effects mediated via the adaptive immune system. To determine whether systemic EGF alters the T-cell response following sepsis, splenic flow cytometry was assayed in mice randomized to receive systemic EGF or vehicle. CD4 + T-cell frequency was increased, whereas CD8 + T-cell frequency was decreased in septic mice following EGF, associated with a significant decrease in activated CD4 + T memory cells. Further, the exhaustion marker TIGIT was significantly upregulated following EGF on both conventional and regulatory CD4 + T cells. Based on these findings and known crosstalk between the gut epithelium and the adaptive immune system, we asked whether the beneficial effects of systemic and intestine-specific EGF were dependent on the presence of an adaptive immune system. Rag1-/- mice lacking mature lymphocytes were randomized to receive either systemic EGF or vehicle following sepsis. In contrast to its beneficial effect in immunocompetent mice, EGF markedly worsened 7-day mortality in Rag1 -/- mice. Similar to immunocompetent mice, EGF decreased gut epithelial apoptosis in Rag1 -/- mice but lost its ability to improve either permeability or villus length. Further, when transgenic mice that overexpress intestine-specific EGF were crossed to Ra g1 -/- mice, intestine-specific EGF had no impact on survival following sepsis despite retaining its ability to decrease sepsis-induced gut epithelial apoptosis and permeability. Thus, although EGF is a potentially novel therapeutic in sepsis via improving gut integrity, EGF also changes T-cell biology, and the survival advantage of EGF following sepsis is dependent, at least in part, on interactions between the gut and the adaptive immune system.