Epithelial decision makers: in search of the 'epimmunome'

Abstract

Frequent microbial and nonmicrobial challenges to epithelial cells trigger discrete pathways, promoting molecular changes such as the secretion of specific cytokines and chemokines and alterations to molecules displayed at the epithelial cell surface. In combination, these molecules impose key decisions on innate and adaptive immune cells. Depending on context, those decisions can be as diverse as those imposed by professional antigen-presenting cells, benefiting the host by balancing immune competence with the avoidance of immunopathology. Nonetheless, this potency of epithelial cells is also consistent with the causal contribution of epithelial dysregulation to myriad inflammatory diseases. This pathogenic axis provides an attractive target for tissue-specific clinical manipulation. In this context, a research goal should be to identify all molecules used by epithelial cells to instruct immune cells. We term this the 'epimmunome'.

Fig 1. Epithelial cells impose diverse decisions on immune cells

Epithelial cells under various conditions express molecular mediators of immune cell instruction. Under relatively non-stressed conditions (top) the dominance of TSLP, IL-25 and other molecules shown instructs T-regulatory and Type-2 responses that, when dysregulated are associated with the diseases shown. As epithelial damage and dysregulation increases, other molecules shift the instructions to T cells toward Type-1 responses, with a different set of associated diseases. The NFκB pathway is utilised by epithelial cells to mount both sets of responses.

Fig 2. molecular axes of epithelial immune cell interactions

Upon exposure to commensals, pathogens, allergens, or physico-chemical dysregulation (1), epithelial cells send instructions via soluble mediators to sub-epithelial DC and lymphocytes (2), to intraepithelial lymphocytes (3), or to specialised subsets of tissue-associated non-epithelial T cells such as human Th-22 cells (4). They also communicate with IEL by stimulatory (5) and co-stimulatory (6) ligand-receptor interactions. T cells reciprocate by expressing cytokines that act upon the epithelial cells (7).