Although the existence of memory T cells in peripheral tissues had long been recognized, it was not known for many years whether these cells were truly tissue resident. Memory T cells had classically been divided into effector memory T (TEM) cells and central memory T (TCM) cells, and it was largely thought that tissue T cells comprised TEM cells in transit through the body. However, it was postulated by David Masopust, Leo Lefrançois and colleagues in 2001 that memory T cells in tissues “either continuously recirculate through peripheral tissues or permanently reside in them” (Masopust et al., 2001). Landmark papers by Gebhardt et al. and Masopust et al., published in 2009 and 2010, signified the advent of tissue-resident memory T (TRM) cells as a distinct T cell subset.

These two studies extended the TEM and TCM cell paradigm by showing that tissue T cells exist in disequilibrium with the circulating T cell populations. They showed that antigen-specific CD8+ T cells with a unique phenotype persist at the site of previous infection — namely, the dorsal root ganglia and skin of herpes simplex virus-infected mice or the intestinal epithelium following infection with lymphocytic choriomeningitis virus. Coincidentally, figure 5 of both papers is central, showing that TRM cells can persist for several weeks as an autonomous population following tissue transplantation. Other studies had provided evidence in support of tissue residency (Boyman et al., 2004), but it was the study by Gebhardt et al. that showed that these TRM cells afford enhanced local protection, which is the defining feature of immunological memory.

Collectively, these studies were instrumental in spawning a renewed focus on regional immunity, persuading me and many others to work in the field of tissue-resident memory. The concept of tissue residency has now been expanded to other lymphocyte populations, even those of the innate immune system, such as natural killer T cells and innate lymphoid cells. The importance of TRM cells is now well accepted and they are emerging as key players in the fight against infection. Their manipulation in therapeutic settings has enormous potential for the clinical modulation of tissue pathologies and has considerable promise for the control of solid organ cancers.