Central Memory CD4 T Cells

Abstract

Memory CD4 Tcells can be divided into central memory (TCM) and effector memory (TEM) subsets, which are endowed with different homing and proliferative capacities as well as distinct effector functions (Sallusto et al. 1999). TCM cells can directly home to secondary lymphoid organs and express the lymphoid homing molecules CD62L (L-selectin) and CCR7 (chemokine receptor 7). In contrast, TEM cells home to tertiary sites and tissues and have direct effector functions upon stimulation, including secretion of inflammatory cytokines such as interferon gamma (IFN-g) and tumor necrosis factor (TNF). Thus, TCM cells define a lymphoid homing subset without immediate effector function, whereas TEM cells are defined as a subpopulation that localize to tissues, with rapidly induced effector function and less proliferative potential. A dominant theory is that TCM represent a precursor to TEM as TCM have greater proliferative potential, are longer lived, and can generate TEM and T effector cells upon stimulation. Furthermore, TCM and TEM homeostatic proliferations are distinct as TCM respond to interleukin 7 (IL-7), whereas TEM respond to interleukin 15 (IL-15). The description of the two Tcell memory subsets led to different models of memory generation. In the “divergent” model of memory T cell formation, naive T cells, after antigen engagement, can directly differentiate into an effector T cell or a memory Tcell. Avariation of this divergent model is the “bifurcation” model, wherein daughter cells of naive T cells have an unequal cell division yielding a memory and an effector cell. This is in contrast to a “linear differentiation” model where effector cells are generated first and subsequently yield memory populations (Ahmed et al. 2009). What controls the memory subset composition in response to infection is not completely understood; however, duration, location, strength, and dose of antigen are thought to play critical roles (Kaech et al. 2002). Later work confirmed the T cell self-renewing properties of TCM previously described, although the exact lineage relationship between effector T cells and the memory subsets in vivo has not been proved. Subsequently, additional subsets have been identified including a transitional memory T cell subset (TTM), an intermediate between TCM and TEM, which does not express CCR7 although retains other markers of TCM cells such as CD27. A stem cell-like memory T cell population (TSCM) that expresses some classical markers of naive T cells (CD45RA+) and of memory T cells (CD95) has also been identified. TSCM cells have multipotency and increased survival and proliferative capacity and can generate all memory T cell subsets including TCM (Gattinoni et al. 2011).