Four functionally distinct populations of human effector-memory CD8+ T lymphocytes

In humans, the pathways of memory and effector T cell differentiation remain poorly defined. We have dissected the functional properties of ex vivo effector-memory (EM) CD45RA(-)CCR7(-) T lymphocytes present within the circulating CD8(+) T cell pool of healthy individuals. Our studies show that EM T cells are heterogeneous and are subdivided based on differential CD27 and CD28 expression into four subsets. EM1 (CD27(+)CD28(+)) and EM4 (CD27(-)CD28(+)) T cells express low levels of effector mediators such as granzyme B and perforin and high levels of CD127/IL-7R alpha. EM, cells also have a relatively short replicative history and display strong ex vivo telomerase activity. Therefore, these cells are closely related to central-memory (CD45RA(-)CCR7(+)) cells. In contrast, EM2 (CD27(+)CD28(-)) and EM3 (CD27(-)CD28(-)) cells express mediators characteristic of effector cells, whereby EM3 cells display stronger ex vivo cytolytic activity and have experienced larger numbers of cell divisions, thus resembling differentiated effector (CD45RA(+)CCR7(-)) cells. These data indicate that progressive up-regulation of cytolytic activity and stepwise loss of CCR7, CD28, and CD27 both characterize CD8(+) T cell differentiation. Finally, memory CD8(+) T cells not only include central-memory cells but also EM, cells, which differ in CCR7 expression and may therefore confer memory functions in lymphoid and peripheral tissues, respectively.