Emerging paradigms of T-cell co-stimulation
Introduction
During the past three years, numerous T-cell co-stimulatory molecules (inducible co-stimulator [ICOS], programmed death-1 [PD-1], B and T lymphocyte attenuator [BTLA]) and their ligands (ICOS-L, PD-L1, PD-L2, BTLA-L, B7 homolog 3 [B7-H3]) have been identified, all of them members of the CD28 and B7 families of molecules. Several recent reviews provide a comprehensive overview of the structure and function of these newly identified co-stimulators and their ligands 1., 2., 3., 4., 5., 6.. Other recent reviews excellently cover the family of co-stimulatory molecules structurally related to the tumor necrosis factor (TNF) receptor, including 4-1BB, OX40, CD27, CD30, herpesvirus entry mediator (HVEM) and their corresponding ligands 7., 8., 9., 10.. Less well defined is the signaling lymphocyte activation molecule (SLAM) family of co-stimulators [11]. More specialized recent reviews focus on the signal transduction properties of T-cell co-stimulators 12., 13. and on the different co-stimulation requirements of CD4+ and CD8+ T cells in antiviral immunity [14].
The newly available information has made it clear that the concepts of T-cell co-stimulation, which were largely based on data obtained with the CD28/cytotoxic T lymphocyte antigen-4 (CTLA-4) system 2., 3., 15., have to be expanded. The elucidation of the relative functional roles of the various co-stimulators is now key to understanding T-cell activation in vivo. In this respect, recent comparative work on the structurally and functionally homologous molecules CD28 and ICOS was particularly informative.
In this review, rather than focusing on a particular family of co-stimulatory molecules, we attempt to extract from the newly available information some general paradigms governing T-cell co-stimulation. It is important to stress that due to the limited space of this review the experimental data for these concepts can only be cited in an exemplary fashion.
Section snippets
Definition of T-cell co-stimulation
As the term is often used loosely, it seems important to define T-cell co-stimulation. T-cell co-stimulatory molecules can be defined as cell-surface molecules that cannot functionally activate T cells on their own, but rather amplify or counteract signals provided by the T-cell receptor (TCR) complex. Cell-surface molecules that improve the adhesion of T cells without modulating the TCR signal are not regarded as co-stimulatory. On the basis of this definition, Table 1 lists several
Basic expression patterns of co-stimulators and their ligands
The large majority of T-cell co-stimulators belong either to the CD28 or the TNF-receptor families of molecules (Table 1). Only a few (CD28, CD27, HVEM) are expressed on T cells in a constitutive fashion, whereas the majority of T-cell co-stimulators are induced only following cell activation subsequent to antigen recognition by the TCR. All of the constitutively expressed co-stimulators have positive amplifying effects, whereas the group of inducible co-stimulators contains positive (ICOS,
Hierarchy and interdependence
The constitutive expression of CD28 already indicates a very early involvement in T-cell activation, whereas the inducible nature of many other co-stimulatory molecules points to a participation in later stages of T-cell activation. Recent data also revealed a hierarchical relationship. Co-stimulation via CD28 was found to strongly augment the induction of ICOS on the T-cell surface [18]. This dependence is not absolute, however, as ICOS can be induced on the T-cell surface in the absence of
Specific gene induction
One could postulate that the various T-cell co-stimulators exert their specific function(s) in the immune system by inducing a specific gene-expression program. Surprisingly, the general rule seems to be that various T-cell co-stimulators modulate large sets of identical genes, and only exceptionally induce specific genes. For example, CD28 co-stimulation significantly modulates the expression of more than 3 000 genes. Of these, approximately half are upregulated, the other half, somewhat
CD4+/CD8+ subset-biased function
T-cell co-stimulatory molecules are not uniformly expressed. CD28, ICOS and CTLA-4 are almost completely restricted to T cells, whereas PD-1, CD27 and BTLA are also expressed on activated B cells, indicating a broader function. Further expression differences can be observed also within T-cell subsets. In vitro, CD4+ T cells upregulate ICOS to a higher degree than CD8+ T cells 18., 19., and ICOS is almost exclusively found on preactivated CD4+ T cells and barely on CD8+ T cells in unchallenged
Coupling of co-stimulator cell surface density to T-cell differentiation/effector status
On analyzing ICOS expression patterns on CD4+ T cells obtained ex vivo in various models, it became apparent that ICOS cell-surface expression is not associated with a particular cytokine pattern. In Schistosoma mansoni, a classical T helper 2 (Th2) model, high ICOS expression correlated with the capacity of CD4+ T cells to generate the Th2 cytokines IL-4, IL-5, IL-13 and IL-10; in Toxoplasma gondii, a Th1 infection model, high ICOS expression strongly correlated with the prototypical Th1
Central versus peripheral co-stimulation
As outlined before, the expression of B7-1 and B7-2, the common ligands for CD28 and CTLA-4, is restricted to professional APCs, at least in humans. By contrast, all other ligands for T-cell co-stimulatory molecules can be found also on endothelial, epithelial and other peripheral tissues (Table 1). This fundamental difference in the tissue distribution of the ligands for CD28 versus the ligands of other co-stimulators points to a basic difference in T-cell co-stimulation in lymphoid organs
Conclusions
In the past, work has centered on the co-stimulation of T cells interacting with professional APCs in lymphoid tissues. With the recognition of an extensive expression of ligands for T-cell co-stimulators on various peripheral tissues, T-cell co-stimulation in the periphery has to come into focus. A fundamental issue is the question of how antigens are presented to T cells in these peripheral interactions. On the whole, there is little doubt that there is a fundamentally different mechanism of
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
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of special interest
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of outstanding interest
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