Chapter Four - A Transendocytosis Perspective on the CD28/CTLA-4 Pathway

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Abstract

T cell activation is a key event in the adaptive immune response and vital to the generation of both cellular and humoral immunity. Activation is required not only for effective CD4 T cell responses but also to provide help for B cells and the generation of cytotoxic T cell responses. Unsurprisingly, impaired T cell activation results in infectious pathology, whereas dysregulated activation can result in autoimmunity. The decision to activate is therefore tightly regulated and the CD28/CTLA-4 pathway represents this apical decision point at the molecular level. In particular, CTLA-4 (CD152) is an essential checkpoint control for autoimmunity; however, the molecular mechanism(s) by which CTLA-4 achieves its regulatory function are not well understood, especially how it functionally intersects with the CD28 pathway. In this chapter, we review the established molecular and cellular concepts relating to CD28 and CTLA-4 biology, and attempt to integrate these by discussing the transendocytosis of ligands as a new model of CTLA-4 function.

Introduction

The central problem confronting the adaptive immune system (T and B cells) is how to generate lymphocytes with a broad enough receptor repertoire in order to recognize all conceivable foreign antigens. The solution to this problem—the random rearrangement of gene segments encoding the T cell receptor and antibodies—generates huge diversity, but initiates a second problem: how to prevent these receptors from recognizing our own tissues and causing autoimmunity? For T cells, this problem is addressed in part during their development in the thymus where highly self-reactive T cells are removed by negative selection (Xing & Hogquist, 2012). Here, a variety of self-antigens are also ectopically expressed on thymic epithelial- and antigen-presenting cells facilitating deletion of overtly self-reactive T cells. In parallel, this process can also result in the generation of a specialized population of regulatory T cells (Treg), which are also essential to self-tolerance (Cowan et al., 2013). The importance of such ectopic antigen expression can be observed in genetic deficiency of the AIRE protein where both mice and humans develop specific autoimmunity (Metzger & Anderson, 2011). However, despite these processes, it is apparent that the T cell repertoire is not entirely purged of self-specificities. Interestingly, recent studies suggest that the frequency of self-reactive specificities within the peripheral T cell repertoire in humans is ultimately rather similar to that for other antigens (Su, Kidd, Han, Kotzin, & Davis, 2013). Indeed, it can be argued that given the likely degree of cross-reactivity required for effective antigen coverage, the removal of all self-specificities is unfeasible (Sewell, 2012). Accordingly, self-tolerance by deletion does not appear to be the only solution and the peripheral T cell repertoire is therefore established in the face of inevitable self-reactivity. The degree of self-reactivity present is spectacularly revealed by a variety of immune defects that result in T cell-dependent autoimmunity. For example, deficits in the TGFβ (Rubtsov & Rudensky, 2007), Foxp3 (Sakaguchi, 2005), IL-2 (Malek & Bayer, 2004), IL-10 (Moore, de Waal Malefyt, Coffman, & O'Garra, 2001), cytotoxic T lymphocyte antigen-4 (CTLA-4) (Walker & Sansom, 2011) as well as other pathways can all lead to profound and often fatal autoimmunity highlighting the lifelong need for immune regulation in the periphery (Kim, Rasmussen, & Rudensky, 2007). Thus, rather than completely purging us of self-reactive T cells, the thymus appears to act to select T cells with constrained self-reactivity which can subsequently be controlled by other mechanisms (Palmer & Naeher, 2009). The selection of a repertoire that responds weakly to self-antigens provides an opportunity to use additional “costimulatory” signals as a mechanism for controlling peripheral T cell activation. Based on this concept, the CD28/CTLA-4 pathway appears to act as a molecular checkpoint ideally placed at the decision point between immunity to potential pathogens and peripheral self-tolerance. Here, we explore this concept in the light of a novel mechanism of CTLA-4 function, transendocytosis.

Section snippets

The CD28 Pathway

CD28 is a 44 kDa, type I transmembrane protein expressed on the surface of the majority of naïve CD4 and CD8 of T cells which consists of a single extracellular Ig-V-like domain assembled as a homodimer. CD28 is well established as a major costimulatory molecule in T cell activation important in the initiation and augmentation of T cell mediated immunity via its interactions with two ligands CD80 and CD86, found predominantly on APC (Fig. 4.1; Keir and Sharpe, 2005, Linsley and Ledbetter, 1993,

CD80 and CD86: The Ligands for CD28 and CTLA-4

All the features of the CD28 signaling pathways outlined above are thought to be triggered upon engagement by two well-described ligands found on antigen-presenting cells, making control of ligand expression another obvious checkpoint for T cell activation. The first identified ligand CD80 (B7/BB1 or B7-1) was described by Linsley et al. (1991). This was followed by the identification of a second ligand CD86 (B7-2) (Azuma, Ito, et al., 1993, Freeman et al., 1993). Until recently, these two

CTLA-4

CTLA-4 is a type I transmembrane glycoprotein homologous to CD28 (Harper et al., 1991). Despite this, CD28 and CTLA-4 share limited identity at protein level being only ~ 30% identical at the amino acid level. Both CD28 and CTLA-4 are colocated on human chromosome 2 along with the ICOS gene as a result of duplication. Notably, both CD28 and CTLA-4 share a conserved hexamer motif MYPPPY that forms part of the ligand-binding site shared by both ligands (Yu et al., 2011). While CD28 and CTLA-4 are

Transendocytosis as a Model of CTLA-4 Function

The above data make a convincing case for a T cell-extrinsic mechanism of suppression mediated by CTLA-4 predominantly expressed by Treg. However, until recently, mechanisms that could deliver such a function have been generally lacking. Based initially on observations, using transfected cell models, we recently observed robust transfer of ligands could occur into CTLA-4-expressing cells (Qureshi et al., 2011). This observation raised the possibility that CTLA-4 could potentially act as a

An Integrated Perspective on CD28 and CTLA-4

The generation of a large and diverse TCR repertoire presents the immune system with an enormous challenge. On one hand, sufficient receptor diversity is required in order recognize and destroy potential pathogens, whereas on the other self-reactive T cells must remain under strict control. Given that in terms of molecular recognition by the TCR, there is no difference between peptides derived from self-antigens and those from pathogens, the regulation of the T cell activation relies on

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