TCM and TEM Are Distinguished by Their Localeand Commitment to Eff ector FunctionA small proportion (less than10%) of the progeny of a naïve cell that has proliferated robustly in response to antigen differentiates into TCM and TEM cells.

In general, these two subsets are distinguished by where they reside as well as their level of commitment to a specific effector cell fate.

In general, TCM cells reside in and travel between secondary lymphoid tissues. They live longer and have the capacity to undergo more divisions than their TEM counterparts. When they reencounter their cognate pathogen in secondary lymphoid tissue, they are rapidly activated and have the capacity to differentiate into a variety of effector T-cell subtypes, depending on the cytokine environment.

On the other hand, TEM cells travel to and between tertiary tissues (including skin, lung, liver, and intestine). They are arguably better situated to contribute to the first line of defense against reinfection because they have already committed to an effector lineage during the primary response and exhibit their effector functions quite rapidly aft er reactivation by their cognate pathogen.

How and When Do Memory Cells Arise?memory cells arise very early in the course of an immune response (e.g., within 3 days), but their cell of origin remains controversial. Some investigations suggest that memory cells arise as soon as naïve T cells are activated.

Others suggest that memory cells arise from more fully differentiated naïve T cells. Still others raise the intriguing possibility that naïve T-cell activation generates a “memory stem cell” that is self-renewing and gives rise to memory eff ector cell populations. These models are not mutually exclusive, and it ispossible that memory cells can arise at several different stages of T-cell activation throughout a primary response.

The relationship between TCM and TEM cells is also debated. They may originate independently from naïve and effector cells, respectively, or may give rise to each other.Studies suggest, in fact, that TCM cells arise from TEM cells, and one possible model of relationships is shown in Figure11-13. Here, investigators speculate that TCM cells arise prior to TEM cells, from cells at an earlier stage of differentiation into effector (helper or cytotoxic) T cells. TEM cells arise late, and also may develop from fully differentiated effector cells.

The model also suggests that effector cells can replenish central memory cells.It should be stressed, however, that several other models have also been advanced. For instance, recent work suggests interactions experienced by effector cells determines their TCM versus TEM fate. Eff ector cells that interact with B cells may preferentially develop into central and not eff ector memory T cells. New models may also need to incorporate intriguing recent observations, including the possibilities that (1) memorycells arise from the asymmetric cell division of activated T cells, where one daughter cell becomes an eff ector cell, and another contributes to the memory pool, and (2) that T-cell activationgenerates a self-renewing memory stem cell population that provides a long-term source of memory T cells.

What Signals Induce Memory CellCommitment?

Most investigators agree that T-cell help is critical to generating long-lasting memory. For instance, CD8_ T cells can be activated in the absence of CD4_ T-cell help, but this “helpless” activation event does not yield long-lived memory CD8_ T cells. Th e relative importance of other variables in driving memory development is still under investigation. Although intensity of T-cell receptor engagement was thought to be a factor in memory cell commitment, recent data suggest that even low-affi nity interactions can generate memory T cells. All studies, however, appear consistent with the recognition that the more proliferation a response inspires, the better the memory pool.Do Memory Cells Refl ect the Heterogeneity ofEff ector Cells Generated during a PrimaryResponse?We have seen that naïve T cells diff erentiate into a wide varietyof eff ector T-cell subpopulations, largely determined bythe cytokine signals they receive during activation. Studiesindicate that the memory cell response is also very diverse,in terms of both the T-cell receptor specifi cities and the arrayof cytokines produced. However, the cellular origin of thisdiversity is still under investigation. Specifi cally, does thisdiverse memory response strictly refl ect the functional eff ectordiversity generated during the primary response? Ordoes it develop anew from central memory T cells respondingto diff erent environmental cues during rechallenge? Th eanswer is likely to be “Both,” but investigations continue.Are There Diff erences between CD4_

and CD8_ Memory T Cells?Th e simple answer is “Maybe.” Memory CD8_ T cells areclearly more prevalent than memory CD4_ T cells. Th is ispartly because CD8_ T cells proliferate more robustly andtherefore generate proportionately more memory T cells. Itmay also be due to diff erences in the life span of memory Tcells: CD4_ memory T cells may not be as long-lived asCD8_ memory T cells.How Are Memory Cells Maintainedover Many Years?Whether memory cells can persist for years in the absence ofantigen remains controversial, although evidence seems tofavor the possibility that they do. Regardless, it does seemthat memory persistence depends on the input of cytokinesthat induce occasional divisions, a process known as homeostaticproliferation, which maintains the pool size by balancingapoptotic events with cell division. Both IL-7 and IL-15appear important in enhancing homeostatic proliferation,but CD4_ and CD8_ memory T-cell requirements may diff er.