Understanding the generation and function of memory
T cell subsets
Antonio Lanzavecchia and Federica Sallusto
Memory Tcellscanbebroadly dividedinto centralmemory and
effector memory subsets, which are endowed with different
capacities to home to lymphoid or non-lymphoid tissues, to
proliferate in response to antigen or cytokines and to perform
effector functions. In the past few years progress has been
made in understanding the properties of these memory T cell
subsets and, in particular, the signals required for their
generation and maintenance. Collectively these data point to a
critical role of central memory T cells in conferring long-term
Institute for Research in Biomedicine, Via Vincenzo Vela 6, CH-6500
Corresponding author: Lanzavecchia, Antonio
Current Opinion in Immunology 2005, 17:326–332
This review comes from a themed issue on
Lymphocyte effector functions
Edited by Lorenzo Moretta
Available online 20th April 2005
0952-7915/$ – see front matter
# 2005 Elsevier Ltd. All rights reserved.
In the past five years it has become increasingly recog-
nized that memory T cells are heterogeneous in terms of
both homing capacity and effector function. This hetero-
geneity is reflected in the current definition of central
memory (TCM) and effector memory (TEM) T cells .
Five years ago we proposed that the two memory popula-
intermediates generated in the primary response that are
arrested at different stages of differentiation . This
model is based on the finding that, depending on the
strength of T-cell receptor (TCR) and cytokine stimula-
tion received, activated T cells progressively acquire
tissue homing receptors, effector function and the capa-
city to respond to homeostatic cytokines, while losing
lymph node homing receptors and proliferative capacity
(Figures 1 and 2).
Three experimental approaches have been taken in
human and mouse systems to dissect the cellular basis
of immunological memory: the phenotypic and functional
characterization of memory T cells under steady state
conditions; the monitoring of memory T-cell develop-
ment in ongoing immune responses; and, the identifica-
tion of the signals necessary for generation of memory
T cells. In this article, we review recent results obtained
using these approaches and discuss them in the context of
our proposed model.
Analysis of memory T cells under steady
In both humans and mice two broad memory T cell
subsets have been delineated according to their homing
capacity and effector function [3–5]. TCMhome to lymph
nodes and have limited effector function, but they pro-
liferate and become effector cells upon secondary stimu-
lation. By contrast TEMhome to peripheral tissues, can
rapidly produce effector cytokines such as IFN-g upon
antigenic stimulation, but have limited proliferative capa-
city. Recent data show that that mouse CD8+TEMare not
obligatory tissue-resident cells, as in parabiosis experi-
ments they rapidly equilibrated into peripheral tissues of
the two parabionts [6?]. The TCM and TEM subsets
realize an effective division of labor in the memory
response: TCMare involved in secondary responses and
long term protection, and TEMare involved in immediate
protection. The existence of TCM and TEM provides
evidence that migratory capacity and effector function
are coordinately regulated in T-cell development. This
concept has been extended by recent studies showing the
simultaneous generation of helper T cells and tissue-
homing inflammatory cells during the same immune
response , and also by the selective imprinting of
skin-homing  or gut-homing receptors  on develop-
ing T cells by dendritic cells (DCs) isolated from skin or
gut, a function that, in the gut, appears to be mediated by
retinoic acid .
Memory T cells as differentiation
Several studies have validated and extended the concept
that memory T cells are intermediates arrested at differ-
ent stages of differentiation [2,11]. Non-effector CD4+T
cells capable of differentiating to Th1 and conferring
long-term protection were defined in the mouse in adop-
tive transfer experiments . Human TCMcapable of
differentiating spontaneously into Th1 or Th2 in the
absence of polarizing cytokines (defined as pre-Th1
and pre-Th2) were identified according to the expression
of CXCR3 and CCR4 [13?]. Furthermore, most human
TEM(both Th1 and Th2) when re-stimulated in vitro
under opposite polarizing conditions, while retaining the
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Lymphocyte effector functions
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