The role of epidermal growth factor in mediating survival in mouse sepsis is dependent upon an intact adaptive immune system

Carolyn M Davis; Caitlin A Fitzgerald; Layla S Jaffree; Yasmin Ali; Timothy K Lee; John D Lyons; Rohit Mittal; Zhe Liang; Greg S Martin; Yvonne Suessmuth; Mandy L Ford; Craig M Coopersmith

doi:10.1097/SHK.0000000000002627

The role of epidermal growth factor in mediating survival in mouse sepsis is dependent upon an intact adaptive immune system

Shock. 2025 May 12. doi: 10.1097/SHK.0000000000002627. Online ahead of print.

Authors

Carolyn M Davis, Caitlin A Fitzgerald, Layla S Jaffree, Yasmin Ali, Timothy K Lee¹, John D Lyons¹, Rohit Mittal, Zhe Liang¹, Greg S Martin², Yvonne Suessmuth³, Mandy L Ford⁴, Craig M Coopersmith¹

Affiliations

¹ Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, USA.
² Department of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, USA.
³ Department of Pediatrics, Bone Marrow Transplant, Emory University School of Medicine, Atlanta, GA, USA.
⁴ Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA.

PMID: 40368370
DOI: 10.1097/SHK.0000000000002627

Abstract

Epidermal growth factor (EGF) has healing effects on the intestinal mucosa and improves survival when administered systemically after the onset of pre-clinical 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 extra-intestinal 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 while 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 upon 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 Rag1-/- 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.

Keywords: Gut; T lymphocyte; TIGIT; apoptosis; intestine; mortality; spleen.