Tissue-resident lymphocytes: weaponized sentinels at barrier surfaces

Tissue-resident immune cells stably localize in tissues largely independent of the circulatory system. While initial studies have focused on the recognition of CD8 (+) tissue-resident memory T (CD8 T (RM)) cells, it is now clear that numerous cell types such as CD4 (+) T cells, gd T cells, innate lymphoid cells and mucosal-associated invariant T (MAIT) cells form stable populations in tissues. They are enriched at the barrier surfaces and within non-lymphoid compartments. They provide an extensive immune network capable of sensing local perturbations of the body’s homeostasis. This positioning enables immune cells to positively influence immune protection against infection and cancer but paradoxically also augment autoimmunity, allergy and chronic inflammatory diseases. Here, we highlight the recent studies across multiple lymphoid immune cell types that have emerged on this research topic and extend our understanding of this important cellular network. In addition, we highlight the areas that remain gaps in our knowledge of the regulation of these cells and how a deeper understanding may result in new ways to ‘target’ these cells to influence disease outcome and treatments.