Understanding the generation and function of memory T cell subsets
Introduction
In the past five years it has become increasingly recognized that memory T cells are heterogeneous in terms of both homing capacity and effector function. This heterogeneity is reflected in the current definition of central memory (TCM) and effector memory (TEM) T cells [1]. Five years ago we proposed that the two memory populations result from the selective survival of effector cells and intermediates generated in the primary response that are arrested at different stages of differentiation [2]. This model is based on the finding that, depending on the strength of T-cell receptor (TCR) and cytokine stimulation received, activated T cells progressively acquire tissue homing receptors, effector function and the capacity to respond to homeostatic cytokines, while losing lymph node homing receptors and proliferative capacity (Figure 1, Figure 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 development in ongoing immune responses; and, the identification 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.
Section snippets
Analysis of memory T cells under steady state conditions
In both humans and mice two broad memory T cell subsets have been delineated according to their homing capacity and effector function [3, 4, 5]. TCM home to lymph nodes and have limited effector function, but they proliferate and become effector cells upon secondary stimulation. By contrast TEM home to peripheral tissues, can rapidly produce effector cytokines such as IFN-γ upon antigenic stimulation, but have limited proliferative capacity. Recent data show that that mouse CD8+ TEM are not
Memory T cells as differentiation intermediates
Several studies have validated and extended the concept that memory T cells are intermediates arrested at different 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 adoptive transfer experiments [12]. Human TCM capable 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
The maintenance of memory T cells and the relationship between TCM and TEM
Memory T cells can persist for a lifetime in the absence of antigen and even MHC molecules. A remarkable example of the persistence of memory lymphocytes is the finding that more than 90% of volunteers vaccinated 25 to 75 years ago maintain cellular immunity against vaccinia virus, which declines slowly with a half life of 8–15 years [25]. Newly generated memory T cells have to compete with pre-existing cells for access to survival factors such as homeostatic cytokines. Thus, their survival
Generation of memory T cells in an ongoing immune response
A logical approach to the study of immunological memory is the analysis of developing memory T cells under different conditions of antigenic stimulation. This approach is well suited to mouse studies and, in recent years, has taken advantage of the possibility of analyzing adoptively transferred TCR transgenic T cells. Although this system has clear advantages, the results may be influenced by the high frequency of responding T cells, which causes competition and therefore limits their
Dissecting the signals required for T-cell fitness
Two potential outcomes confront antigen-stimulated naïve T cells: differentiation into effector and memory cells, or deletion. There is convincing evidence that the outcome depends on the strength of antigenic and cytokine stimulation that T cells receive [41]. Human and mouse CD4+ and CD8+ T cells receiving either weak or short antigenic stimulation proliferate initially, but fail to survive both in vitro and in vivo, as they fail to acquire the cardinal features of memory cells, namely the
Conclusions and perspectives for vaccination
There is increasing evidence that TCM have a greater capacity than TEM to persist in vivo and are more efficient in mediating protection because of their high proliferative potential. This is certainly true for the cases in which protection relies on a secondary response. In other conditions, however, protection might require pre-existing levels of competent effector T cells. This is illustrated by the findings in Leishmania major infection, in which protective immunity is mediated by either
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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