When naive T cells find their cognate antigen in the context of appropriate costimulatory signals, usually provided by dendritic cells (DC), they are activated, proliferate, and differentiate into effector or memory T cells. Antigen-experienced T cells differ significantly from naive T cells in their migratory properties. In particular, the former migrate much better to nonlymphoid tissues and sites of inflammation (Mackay et al. 1990; Masopust et al. 2001; Reinhardt et al. 2001; Weninger et al. 2001). In addition, memory cells can be further divided into two main categories, based on distinct migratory and functional characteristics (Sallusto et al. 1999) (Fig. 1A and Table 1). The central-memory T cells (TCM) maintain the expression of L-selectin and CCR7 and, like naive T cells, can migrate into secondary lymphoid organs (Weninger et al. 2001). In addition, TCM upregulate inflammation-seeking traffic molecules and also express high levels of CXCR4, which allows them to migrate efficiently to sites where the CXCR4 ligand CXCL12 is highly expressed, such as the bone marrow (Mazo et al. 2005) and also PLN (Scimone et al. 2004). Consistent with their memory status, TCM express IL-7Ra (Kaech et al. 2003) and can respond faster and more vigorously than naive T cells when reencountering cognate antigen (Manjunath et al. 2001; Sallusto et al. 1999; Wherry et al. 2003).
In contrast to CCR7+ TCM, effector T cells (TEFF, short-lived) and effector memory T cells (TEM, long-lived IL-7Ra+) do not express CCR7, and most are also L-selectin-. Therefore, TEM and TEFF cannot recirculate efficiently through LN or PP (Sallusto et al. 1999; Weninger et al. 2001). However, they migrate efficiently to peripheral/nonlymphoid tissues, like liver, lungs, skin, gut lamina propria, and sites of inflammation (Masopust et al. 2001; Reinhardt et al. 2001; Sallusto et al. 1999; Weninger et al. 2001). In addition, in some assays, only TEFF and TEM, but not TCM, have immediate effector/cytotoxic activity (Manjunath et al. 2001; Sallusto et al., 1999). However, it should be cautioned that, in some studies, in vivo differentiated T cells with a TCM phenotype have been observed to exert effector functions as rapidly and efficiently as TEM (Debes et al. 2002; Unsoeld et al. 2002), and TCM that arise after viral infections are superior to TEM at conferring long-lived antiviral protection (Wherry et al., 2003). It should also be pointed out that in vivo generated TCM can be CCR7+ and simultaneously express homing receptors for peripheral tissues, such as the skin and the gut. Indeed, although a CCR7+ and L-selectinHlgh phenotype is predictive of a memory cell's capacity to home to LN, this does not preclude that such cells can also infiltrate peripheral tissues (Campbell et al. 2001). Given these observations, the distinctions between TCM and Tem can be rather subtle. In the absence of a broad consensus on defining functional subset characteristics, we will refer to TCM as antigen-experienced T cells with PLN homing capacity (i.e., memory marker-expressing T cells that are L-selectinHigh and CCR7+), whereas TEM and TEFF are memory cells that lack either one or both of these homing receptors.
We recently described a method to differentiate and expand CD8 T cells with a Tcm or TEFF phenotype by activating naive T cells with antigen for 48 h followed by culture for at least 5 days in IL-15 or IL-2, respectively (Manjunath et al. 2001). This strategy has allowed us to characterize the in vivo migratory properties of each T cell subset and to perform intravital microscopy (IVM) to dissect the molecular mechanisms involved in the interaction of these cells with PLN HEV and microvessels in bone marrow and inflamed tissues (Goodarzi et al. 2003; Mazo et al. 2005; Scimone et al. 2004; Weninger et al. 2001) (Table 1).
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