TCM and TEM Are Distinguished by Their Locale

and Commitment to Eff ector Function

A small proportion (less than10%) of the progeny of a nave cell that has proliferated
robustly in response to antigen differentiates into T CM 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 T EM 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 nave T cells are activated.
Others suggest that memory cells arise from more fully differentiated nave T cells. Still
others raise the intriguing possibility that nave 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 is
possible 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 nave 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 Figure
11-13. 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. T EM 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 activation
generates a self-renewing memory stem cell population that provides a long-term source of
memory T cells.

What Signals Induce Memory Cell

Commitment?

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 of

Eff ector Cells Generated during a Primary
Response?
We have seen that nave T cells diff erentiate into a wide variety
of eff ector T-cell subpopulations, largely determined by
the cytokine signals they receive during activation. Studies
indicate 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 this
diversity is still under investigation. Specifi cally, does this
diverse memory response strictly refl ect the functional eff ector
diversity generated during the primary response? Or
does it develop anew from central memory T cells responding
to diff erent environmental cues during rechallenge? Th e
answer 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 are
clearly more prevalent than memory CD4_ T cells. Th is is
partly because CD8_ T cells proliferate more robustly and
therefore generate proportionately more memory T cells. It
may also be due to diff erences in the life span of memory T
cells: CD4_ memory T cells may not be as long-lived as
CD8_ memory T cells.

How Are Memory Cells Maintained

over Many Years?
Whether memory cells can persist for years in the absence of
antigen remains controversial, although evidence seems to
favor the possibility that they do. Regardless, it does seem
that memory persistence depends on the input of cytokines
that induce occasional divisions, a process known as homeostatic
proliferation, which maintains the pool size by balancing
apoptotic events with cell division. Both IL-7 and IL-15
appear important in enhancing homeostatic proliferation,
but CD4_ and CD8_ memory T-cell requirements may diff er.