Project Summary It has become clear that a subset of T lymphocytes, called “resident memory” T cells (TRM), is tremendously important for preventing infection by pathogenic microbes through “barrier” tissues, such as the skin, lungs, gut and reproductive tract. These T cells directly kill infected cells, or recruit other immune cells to assist in protecting these tissues. In contrast to the well-studied “migratory” memory T cells (which transit through the blood and lymph in order to hunt for sites of infection), resident memory T cells do not leave the barrier tissues. Since these cells can be so valuable for protective immunity, directed generation of TRM provides an exciting opportunity to enhance vaccines. Similarly, TRM-like cells in tumors have also been found to correlate with a good prognosis. At the same time, TRM are not always a good thing – they are associated with various autoimmune and inflammatory responses (for example psoriasis), hence there are some occasions when it would be valuable to displace TRM from tissues. Interestingly, we recently found that another population of T cells, called “germinal center follicular helpers” (GC-TFH) have some of the same properties as TRM – although these cells live in lymphoid tissues like the lymph node, not barrier tissues. However, the molecular “rules” that determine whether a T cell will be resident versus migratory are unclear – existing data is confusing and contradictory. The fact that some factors are coordinately expressed in various resident T cell populations started us thinking that there may be core molecular mechanisms that distinguish all the different resident T cell types from all the migratory T cell types. This proposal explores that hypothesis. We focus on a panel of factors that are differentially expressed by migratory and resident T cells, but the function of which is incompletely understood. Through sophisticated genetic tools, we will explore what these factors do in numerous situations (involving different T cell populations and diverse infectious models). This involves experiments where we can induce increased or decreased expression of these factors at the timing of our choice (e.g. when cells first arrive in the gut – or 30 days later), and in the location of our choice (e.g. just the cells in the skin, not the cells in the blood).