Emerging paradigms of T-cell co-stimulation

https://doi.org/10.1016/j.coi.2004.03.002Get rights and content

Abstract

The analysis of recent data reveals that T-cell co-stimulation is a hierarchical process with elements of mutual interdependence between individual co-stimulators. The expression and function of co-stimulatory molecules is biased on various T-cell subsets and is dependent on the T-cell differentiation state. The classical paradigm of T-cell co-stimulation by professional antigen-presenting cells has to incorporate the newly recognized concept of T-cell co-stimulation in the interaction with peripheral tissues, such as endothelial or epithelial cells. The two signal paradigm of T-cell co-stimulation is being replaced by a multisignal integration concept of central and peripheral 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:

  • of special interest

  • ••

    of outstanding interest

References (49)

  • A.H Sharpe et al.

    The B7-CD28 superfamily

    Nat Rev Immunol

    (2002)
  • B.M Carreno et al.

    The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses

    Annu Rev Immunol

    (2002)
  • M Croft

    Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?

    Nat Rev Immunol

    (2003)
  • M Tarkowski

    Expression and a role of CD30 in regulation of T-cell activity

    Curr Opin Hematol

    (2003)
  • K.A Frauwirth et al.

    Activation and inhibition of lymphocytes by costimulation

    J Clin Invest

    (2002)
  • C.E Rudd et al.

    Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling

    Nat Rev Immunol

    (2003)
  • B Salomon et al.

    Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation

    Annu Rev Immunol

    (2001)
  • J.C Schwartz et al.

    Structural mechanisms of costimulation

    Nat Immunol

    (2002)
  • K.C Beier et al.

    Induction, binding specificity and function of human ICOS

    Eur J Immunol

    (2000)
  • A.J McAdam et al.

    Mouse inducible costimulatory molecule (ICOS) expression is enhanced by CD28 costimulation and regulates differentiation of CD4+ T cells

    J Immunol

    (2000)
  • E.N Villegas et al.

    A role for inducible costimulator protein in the CD28-independent mechanism of resistance to Toxoplasma gondii

    J Immunol

    (2002)
  • L.S Walker et al.

    Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers

    J Exp Med

    (1999)
  • A Hutloff et al.

    ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28

    Nature

    (1999)
  • A.J McAdam et al.

    ICOS is critical for CD40-mediated antibody class switching

    Nature

    (2001)
  • Cited by (0)

    View full text