Memory T cells: death by acquisition

In this issue of Blood, Mostböck and colleagues report that effector and rested memory T cells can acquire major histocompatibility complex (MHC)/CD80 costimulatory cell complexes (antigen presentasomes [APSs]) from antigen-presenting cells (APCs). This, in turn, provides an important checkpoint of memory T-cell homeostasis through apoptosis of the majority of effector T cells by clonal deletion, possibly allowing the surviving cells to become long-term memory T cells by default.

It is well established that the pool of peripheral lymphocytes is closely regulated and remains relatively constant in the absence of disease. However, during an immune response, the expansion of the T-cell pool is followed by a deletion of most of the newly generated effector cells, thereby restoring the total number of T cells to normal levels.¹  The mechanisms involved in the elimination of effector cells that might play a role in the immunoregulation of T-cell responses have been investigated by Sabzevari and colleagues and described in a series of reports (Sabzevari et al,²  Tatari-Calderone et al,³  and Zhou et al⁴ ). Initially, these investigators demonstrated for the first time that (1) naive T cells, following acquisition of CD80 from antigen-presenting cells (APCs), were themselves capable of acting as APCs; and (2) memory T cells that acquired CD80 in this same fashion did undergo apoptosis in the presence of increased signal 1 mediated via a peptide-MHC on the APCs. These data demonstrated both immunostimulatory and immunoregulatory functions as a result of CD80 acquisition by different T-cell populations.² 

In a follow-up study,³  these investigators were first to demonstrate that human CD4⁺ T cells can acquire CD80 upon activation with autologous or allogeneic APCs. This acquisition was mediated through CD28 receptors and played a key role, both in the activation of cells that acquired these molecules and in adjacent T cells. These findings suggested that acquisition of CD80 by T cells could play a role in regulating immune responses to pathogens or diseases of the immune system. The functional relevance of acquired CD80 by T cells was addressed by a study defining the role of this phenomenon in T-cell clonal expansion.⁴  A series of elegant experiments indicated that upon encountering professional APCs, naive T cells can remove an MHC/CD80 complex and that this “antigen presentasome” (APS) can sustain activation even after T cells have lost contact with APCs. This is a unique concept, since by such a mechanism naive T cells can sustain their activation via continued proliferation and interaction with neighboring naive T cells even in the absence of APCs. In fact, this mechanism allows for a maximum activation of T cells despite the limited duration of their contact with APCs and permits optimal and faster clonal expansion in vivo.

The current paper by Mostböck and colleagues in this issue of Blood indicates that effector and rested memory T cells can acquire the antigen presentasome consisting of MHC/CD80 molecules upon activation in vitro and after vaccination in vivo. This acquisition correlated with increased levels of cell death in vivo and up-regulation of caspase-3, bcl-x, bak, and bax in vitro. In addition, once memory T cells acquired the APS, they became cytotoxic T lymphocytes (CTLs) and killed other cells through perforin-mediated lysis while retaining the production of interferon γ and Th2 type cytokines. In fact, the acquisition of APS by memory T cells might be an important checkpoint leading to the clonal deletion of the majority of effector T cells, while allowing the surviving cells to become long-term memory cells by default (see figure).

In this regard, Sprent and Tough¹  hypothesized that long-term memory cells are generated by a default pathway and represent a few memory T-cell escapees that evaded cell death via multiple mechanisms. In view of this hypothesis, Mostböck and colleagues now suggest that acquisition of the APS by T cells at an early phase of activation leads to the activation and proliferation of such cells. However, once T cells enter the memory phase and acquire more APS, they may well start to interact with one another. In turn, this interaction among memory CD4/CD80^acq T cells could lead to the eradication of the majority of such cells through replicative cessation or even CTL mechanisms. The few activated T cells that did not come in contact with the memory CD4/CD80^acq T cells can be regarded as the few escapees that will turn into long-term memory T cells. Therefore, the acquisition of the antigen presentasome can act as a unique checkpoint for memory CD4 T-cell homeostasis, which ultimately decides the outcome of CD4 T-cell activation.