CD69 guides CD4+T cells to the seat of memory

Immunologists’ views on the cellular basis of immune memory have undergone substantial modifications over the last decade, with new findings advancing the field from mostly descriptive studies of their presumptive phenotypes to those that allow the features distinguishing memory cells from short-lived effectors to be known and understood (1). Although such studies have helped to define the functional qualities of memory cells, more recent attention has been paid to the “where” of immune memory through comparison of the number and quality of memory T and B cells in various anatomical sites. These studies have produced the rather surprising finding that, rather than residing in the secondary lymphoid organs where most immune responses are initiated, many types of memory cells have been shown to preferentially accumulate in the bone marrow (BM), a site more often associated with hematopoiesis (2). As expected, such observations immediately lead back to the question of “how” this process occurs in terms of homing behavior and retention within specialized niches. In PNAS, Shinoda et al. provide a compelling answer for CD4+ memory T cells by showing that expression of the activation marker CD69 is critical for the persistence of CD4+ T cell memory in the bone marrow environment (3). CD4+ memory T cells are critical for the generation of high-affinity memory B cells, long-lived plasma cells, and memory CD8+ T cells, a fact that makes them essential to maintaining protective immunity to many classes of infectious pathogens (4⇓–6). Despite this important immunoregulatory role, there is still much to discover about the differentiation, diversity, and maintenance of CD4+ memory T cells in the body. Following immunization, CD4+ T-cell responses involve an initial clonal expansion that produces the various specialized effector cells needed to deal with the specific antigenic …