Understanding the CD28/CTLA-4 (CD152) Pathway and Its Implications for Costimulatory Blockade

Abstract

T cell activation is a key event in the adaptive immune system and vital in the generation of protective cellular and humoral immunity. Activation is required to generate CD4 effector T cell responses and provide help for B cell and cytotoxic T cell responses. While defective T responses to foreign antigen result in infectious pathology, over-reactive T cell responses against self-antigens result in autoimmunity and, in a transplantation setting, tissue rejection. Understanding how T cell activation is normally regulated is critical to therapeutic intervention and the CD28/CTLA-4 (CD152) pathway represents the initial activation checkpoint in molecular terms. In particular, while the CTLA-4 pathway is well established as an essential regulator of self-reactivity, its mechanism of action is still uncertain. Such mechanistic issues are important given its central position in T cell activation and the increasing number of therapeutic modalities aimed at manipulating the CD28/CTLA-4 pathway. Here, we provide an updated view of CTLA-4 biology, reviewing the established features of the system and highlighting its interplay with CD28. We then discuss how recent progress in our understanding of this pathway affects our interpretations following intervention. A Functional Overview of the CD28/CTLA-4 Pathway CD28 is expressed on the surface of the majority of na€ ıve CD4 and CD8 T cells and is the major costimulatory molecule in initial T cell activation. Together with engagement of the T cell receptor CD28 ligation results in the augmentation of many aspects of T cell-mediated immunity (1-3). Consequently, mice deficient in CD28 show an array of immune defects including impaired T cell activation, a lack of T cell help for B cells and poor memory T cell responses, all highlighting the importance of CD28 costimulation in the generation of effective T cell responses and immune memory.The immune stimulatory features of the CD28 pathway are triggered by engagement of two well-described ligands found on antigen-presenting cells (4). The two ligands CD80 (B7/BB1 or B7-1) and CD86 (B7-2) were, until recently, thought to be the sole ligands for CD28 and CTLA-4; however, there are recent reports that human (but not mouse) CD28 and CTLA-4, can also bind to the ICOS ligand (5). In addition, the PD-1 ligand, PD-L1 can also interact with CD80 (6). The significance of these novel interactions is still emerging and will not be discussed further here. Importantly, the expression of CD80 and CD86 is up-regulated in response to inflammatory stimuli including Toll-like receptor stimulation. As such, up-regulation of ligands is seen as a key link between innate ''danger'' signals and the triggering of an effective adaptive immune response (7). Despite structural and affinity differences (8) which would suggest functional differences, to date, the current view is that CD80 and CD86 have largely redundant or overlapping functions as represented in Figure 1 (9,10).In addition to binding to CD28, both CD80 and CD86 also bind to the inhibitory p...

Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7

“…The cell extrinsic function of CTLA-4 on either conventional or regulatory T cells inhibits binding of CD28 to B7 by a variety of mechanisms and may also downmodulate APC functionality by generating a negative regulatory signal through B7 ligation. In contrast, induced expression of CTLA-4 on the surface of conventional T cells appears to counterbalance activation in a cell-intrinsic manner by negative regulatory signaling at the synapse [7,8,11,12]. Our data suggest that DC-expressed and -secreted CTLA-4 could function in a manner most similar to the former, that is, by binding to APC-expressed B7 in an autocrine and paracrine manner that interferes with CD28 engagement.…”

“…Cell-intrinsic function is thought to be less critical to immune homeostasis since CTLA-4-deficient cells in bone marrow (BM) chimeras with CTLA-4-sufficient cells do not become hyperactivated, yet also likely plays an important role in controlling effector T cell function by recruitment of SHP-2 and PPA2 negative regulatory phosphatases to the YVKM motif in its cytoplasmic tail. CTLA-4 is also believed to play a role in central tolerance by determining signal strength at the immune synapse during thymic selection [7,8,[11][12][13]. A soluble isoform, often found in the sera of autoimmune disease patients, has also been reported to exist, although the precise function of this isoform has yet to be definitively determined [14][15][16][17].…”

Aplastic anemia is related to alterations in T cell receptor signaling

“…CD28 is an important costimulatory molecule that provides a second signal that permits full T cell activation. Upon T cell activation, CTLA-4 is induced and outcompetes CD28 for ligands, thereby preventing excessive T cell activation (25,26). Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING finger E3 ubiquitin-protein ligase, is critical for establishing the threshold for T cell activation (27).…”

Problems of Cancer Treatment. Part I. Theory of Treatment Based on Known Mechanisms of Anticancer Immunological Responses

“…The proteases degrade components of the intercellular matrix and basement membranes of epithelium, which promotes invasion of neoplastic cells and their appearance in the circulation [39,123]. MMP represent endoproteases synthetised in precursor forms and activated by proteases such as plasmin.…”