The Potential of Intraepithelial Lymphocytes as Immunological Targets for the Induction of Innate and Adaptive Memory Responses Through Mucosal Vaccination and Prime Boost

The mucosal surfaces of the different tracts of the human body occupy a vast interface (around 400 m2), and defense at these sites represents the first line of immune defense. It is at the interface of these surfaces that a cellular and molecular crosstalk among different players is accomplished: the microbiota, the mucosal epithelial, and the immune system. Different lymphocyte populations are present on these surfaces as sentinels, ready to act upon any insult that threatens body homeostasis. One of them are the T-cell-derived intraepithelial lymphocytes (T-IELs), gatekeepers at the mucosal epithelium of the common mucosal system (MALT) (gut, lung, and urogenital tract). These lymphocytes are divided into natural, non-conventional (CD4+/CD8+, TCR αβ, γδ, αα) and induced T-IELs or conventional (CD4+/CD8+ TCR αβ). The most remarkable and distinguishing properties of these innate lymphocyte populations are a triad of attributes: innate, cytotoxic, and memory-protective immune responses. T-IELs are a disregarded population of innate cells, ready to act, for rapid microbial clearance, and an effective support for any mucosal invader. Despite this, T-IELs are an underutilized immunological target that needs further in-depth investigation into their role in inducing fast, rapid clearance of mucosal pathogens, and protective and immune memory (innate and adaptive). The present commentary aims to put into context this emerging potential of T-IELs as immunological targets.