(left) The chart shows the relative longevity and recall expansion potential of “idealized” naïve, effector, Tcm and Tem cell populations, as they are typically discussed, as well as conflicting models of lineage differentiation. (right) The same chart is shown with inclusion of some populations found during actual immune responses. The shaded area indicates a distribution “cloud” of cells with effector-through-memory like properties. Many populations in this cloud would typically be designated “Tem” but, as indicated, there is also diversity among the “Tcm” cell pool. Shown are memory populations identified in various tissue sites, including Tem cells from lung bronchoalveolar lavage (BAL) (Ely et al., 2003) and small intestine (SI)(Masopust et al., 2006b) and Tem and Tcm cells isolated from spleen at different memory time points (“Early” and “Late” Tcm and Tem) (Roberts et al., 2005). Also shown are CD8⁺ T cells primed without sufficient CD4⁺ T cell help (“Helpless”), memory-like cells made through lymphopenia-driven homeostatic proliferation (“HP” memory cells), T cells driven to “exhaustion” by chronic antigen exposure (“Tex”) and effector cells maintained into the long-lived phase (“Persistent effector”) (references provided in the main text). The position of CD8⁺ memory T cells produced in IL-15- (or IL-15Ra-) deficient mice, and of CD25-deficient CD8⁺ memory T cells is also illustrated, though it is not yet clear whether such cells are representative of populations generated in natural responses (hence these cells fall outside the “cloud”). Relative positions of populations are not intended to be precise, but merely to indicate the diversity of groups identified using only these two parameters. The box indicates further layers of complexity would be revealed if additional functional parameters (some of which are listed here) were included in the subset definitions.

The schematic shows numbers of antigen specific T cells (black line) at various stages after priming and boosting of a prototypical acute immune response. During the primary response, the fate of typical effector (red line) and memory (green line) cells is shown. Also shown are populations of intermediate longevity whom may also contribute to protection form re-infection (maroon and gold lines).

After stimulation of naïve T cells by antigen bearing APC, the first cell division is asymmetric and may produce cells with distinct potential to become effector or memory cells (indicated by shading of daughter cells). However, the products of initial stages of the expansion phase (“Early effectors”) probably all express key effector molecules (including Granzyme B in CD8⁺ T cells and IFN-γ in CD8⁺ T and Th1 cells), yet lack later effector markers. This early effector pool may have full or only limited potential to become any of the differentiated populations shown on the right. The production of effector and memory populations during the remainder of the expansion phase is also conditioned by the duration and intensity of various signals. These include signaling associated with the TCR and also cytokine receptors. Such signals may dictate expression of key transcription factors including T-bet and Blimp-1, and also control the metabolic status of the activated cell (including that regulated by mTOR activity). Unusually strong or persistent stimuli may generate “exhausted” T cells, whereas inadequate stimuli produces “unfit” cells. In between these extremes, effector and memory differentiation may be driven by cumulative cues operating on the early effector cell (or by selectively favoring outgrowth/survival of cells with a bias toward the effector or memory fate).