Confusing signals: recent progress in CTLA-4 biology

Abstract

The mechanism of action of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remains surprisingly unclear. Regulatory T (Treg) cells can use CTLA-4 to elicit suppression; however, CTLA-4 also operates in conventional T cells, reputedly by triggering inhibitory signals. Recently, interactions mediated via the CTLA-4 cytoplasmic domain have been shown to preferentially affect Treg cells, yet other evidence suggests that the extracellular domain of CTLA-4 is sufficient to elicit suppression. Here, we discuss these paradoxical findings in the context of CTLA-4-mediated ligand regulation. We propose that the function of CTLA-4 cytoplasmic domain is not to transmit inhibitory signals but to precisely control the turnover, cellular location, and membrane delivery of CTLA-4 to facilitate its central function: regulating the access of CD28 to their shared ligands.

Keywords: CD28; CTLA-4; T cell activation; T cell tolerance; costimulation.

Figure 1

The CD28 and CTLA-4 receptors are connected by shared ligands. CD28 and CTLA-4 on the T cell bind to two ligands, CD80 and CD86, on antigen-presenting cells (APCs). The interactions take place with varying affinities (represented by thickness of the arrows). Given that CTLA-4 has higher affinity for both ligands, this sets up a competition between CTLA-4 and CD28 for ligand binding. The system is integrated in the sense that alteration of one component has the potential to affect the equilibrium of the other interactions. For example, blockade or deletion of CTLA-4 will lead to increased availability of ligands for CD28 binding and vice versa. Abbreviations: Tconv, conventional T cells; TCR, T cell receptor.

Figure 2

The various forms of ligand competition. The figure depicts three variations on the theme of competition between CD28 and CTLA-4 for access to ligand (drawn generically as CD80/86). (A) Activated T cells express both CD28 and CTLA-4, establishing a cell intrinsic competition for ligand access. Note that experiments from bone marrow chimeric mice suggest that this intrinsic role has a relatively minor role on T cell function in vivo. Nonetheless, this form of competition may have significant effects in some experimental settings. (B) Regulatory T cells (Treg) expressing CTLA-4 contact antigen-presenting cells (APC) and physically sequester ligands. This is a form of extrinsic ligand competition as well as cellular competition, because both Treg and conventional T cells (Tconv) are competing for the same APC simultaneously. (C) CTLA-4 removes ligands from the APC via transendocytosis. This is a form of cell extrinsic competition that is spatially and temporally separated from the activation of Tconv. In this model, CTLA-4-expressing Treg continually interact with APCs, remove ligands, and then detach. The APC is unable to provide CD28 costimulation until ligand re-expression occurs. Experiments from bone marrow chimeric mice suggest that cell extrinsic functions provide the major part of CTLA-4 function in vivo. Note that cell extrinsic regulation can be carried out by Tconv as well as by Treg, albeit with Treg having higher levels of CTLA-4 and providing more robust regulation . Abbreviations: DC, dendritic cell; HLA, human leukocyte antigen; TCR, T cell receptor.

Figure 3

Identified cytoplasmic domain motifs involved in CTLA-4 trafficking and cellular localization. The amino acid sequence of the CTLA-4 cytoplasmic domain is shown in single-letter code. Reported motifs involved in cellular localization are shown in color, whereas associations and/or functions that require the CTLA-4 cytoplasmic domain but for which the specific motifs are not defined are shown in black. For definition of abbreviations, please see main text.