Epithelial damage and tissue γδ T cells promote a unique tumor-protective IgE response

IgE is an ancient and conserved immunoglobulin isotype with potent immune function. Nevertheless, the regulation of IgE responses remains enigmatic and evidence for a role of IgE in host defense is limited. Herein we describe that topical exposure to a common environmental DNA-damaging xenobiotic initiated stress-surveillance by γδTCR(+) intraepithelial lymphocytes resulting in class-switching to IgE in B cells and accumulation of autoreactive IgE. High-throughput antibody sequencing revealed that γδ T cells shaped the IgE repertoire by supporting specific VDJ rearrangements with unique CDRH3 characteristics. This endogenous IgE response, via the FcεRI, protected against epithelial carcinogenesis and FceR1a expression in human squamous cell carcinoma correlated with good disease prognosis. This data indicate a joint role for T and B cell immune-surveillance in epithelial tissues and suggests that IgE is part of the host defense against epithelial damage and tumor development.