Future therapies in lung transplantation
Wickii T. Vigneswaran, Edward R. Garrity, John A. Odell in LUNG Transplantation, 2016
CD28 belongs to the immunoglobulin superfamily and is expressed on the surface of T cells. It binds to B7.1 (CD80) and B7.2 (CD86) on APCs to facilitate T-cell activation and proliferation. Specifically, interaction between CD28 and B7 results in increased T-cell proliferation, production of interleukin-2 [IL-2], expression of the antiapoptotic protein Bcl-xL, and increased expression of CD154 (discussed later) on T cells. Blocking these effects would seemingly be desirable in terms of allograft acceptance. However, in addition to binding CD28, B7 (CD80/CD86) is also able to bind with higher avidity and affinity to CTLA4 on T cells. This interaction, in contrast to the interaction between CD28 and B7, inhibits T-cell proliferation and has peripheral tolerogenic effects, the mechanisms of which are not fully understood. CTLA4 expression is induced in activated T cells (presumably as a negative feedback mechanism), and it is expressed constitutively in certain regulatory T cells. Blocking the tolerogenic effects of interaction of CTLA4 with B7 is not desirable from the standpoint of allograft acceptance. However, the implications of interaction between CTLA4 and B7 were not known when the initial attempts to block CD28-B7 began.
T Cells:Regulation and Cellular Immunity
Constantin A. Bona, Francisco A. Bonilla in Textbook of Immunology, 2019
Binding of TCR-CD3 without engaging any co-stimulating molecules leads to a state of anergy (unresponsiveness or refractoriness to activation) and possibly even to deletion by apoptosis (death). The manner in which co-stimulation converts anergy to activation is not known. The interaction between CD28 and B7 expressed on B cells or APC is a very potent co-stimulatory system. Binding of CD28 on a resting T cell will not activate it, but once a T cell has been “primed” by antigen exposure, CD28 can trigger production of IL-2, IL-2R and cellular proliferation. A low level of CD28 binding activates through calcium and PLC-independent pathways. When more CD28 is immobilized on the cell surface, calcium fluxes and PLC are activated. One or more protein tyrosine kinases mediate these signals, at least in part. IL-1 is also released by antigen-presenting cells during antigenspecific T cell activation and may play a co-stimulatory role by increasing T cell production of IL-2 and expression of IL-2R. Whether or not IL-1 is ever actually required for activation to proceed is unclear.
Primary Biliary Cirrhosis Bench to Bedside
Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso in The Pathophysiology of Biliary Epithelia, 2020
Current evidence suggests that Τ cell receptor (TCR) recognition of antigen bound to the major histcompatibility complex (Ag-MHC) is insufficient to lead to Τ cell proliferation or effector function. There is also a requirement for so-called ‘costimulatory’ or ‘accessory’ signals in addition to TCR ligation by Ag-MHC.10,11 Cell-to-cell adhesions via ICAM-1 and LFA-1 or Mac-1, VCAM-1 and VLA-4, and LFA-3 and CD2 are well known as contributors to antigen nonspecific binding. In contrast, costimulatory factors such as the B7 families and its ligands CD28 and CTLA 4 are also significantly involved as second signals that are important for the activation of antigen-specific Τ cells.10–14 B7-1 is normally expressed at low levels in professional antigen presenting cells, including dendritic cells. B7-2 is constitutionally expressed on the surfaces of dendritic cells and macrophages, and is rapidly up-regulated in Β cells by the stimulation via the immunoglobulin receptor or in concert with cytokines. In fact, B7-2 is the major CD28 ligand which is activated in the clonal expansion of antigen-specific Τ cells.
Increases of CD80 and CD86 Expression on Peripheral Blood Cells and their Gene Polymorphisms in Autoimmune Thyroid Disease
Published in Immunological Investigations, 2020
Ayano Watanabe, Naoya Inoue, Mikio Watanabe, Mayu Yamamoto, Haruka Ozaki, Yoh Hidaka, Yoshinori Iwatani
For T-cell activation and differentiation, two signals are required. The first signal is a T cell receptor (TCR) signal recognition of antigen-MHC complex on antigen-presenting cells (APC) (Norcross 1984). However, when T cells receive only this signal, they are not activated but induced to anergy (Smith et al. 2014). The second signal, a costimulatory signal by the accessory molecules on APC, is necessary for T-cell activation and differentiation (Janeway and Bottomly 1994; Jenkins 1994). We previously showed that CD58, a costimulatory molecule, was associated with the AITD susceptibility (Yamamoto et al. 2019). CD28 is the major costimulatory receptor on T cells. It binds to CD80 (B7.1) and CD86 (B7.2) on APC and promotes T cell proliferation and cytokine production in cooperation with the TCR signal (Lanier et al. 1995). Once T cells are activated, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), which has a much higher affinity for CD80 and CD86 than CD28, is expressed on activated T cells (Leung et al. 1995; McCoy and Le Gros 1999), and contributes to downregulation of T cell proliferation (Gao et al. 2011).
A dermatologist perspective in the pharmacological treatment of patients with psoriasis and psoriatic arthritis
Published in Expert Review of Clinical Pharmacology, 2020
Francesco Bellinato, Paolo Gisondi, Giampiero Girolomoni
CD28 is a co-stimulatory receptor for CD80/CD86 expressed on T lymphocytes employed in T cell activation. Antigen-presenting cells (APCs) process and present antigen to T cells and provide co-stimulatory signal through CD80 or CD86. By selectively targeting the CD28 costimulatory signal required for T-cell activation, these drugs block the process that triggers the inflammatory cascade. Abatacept is a soluble fully human fusion protein consisting of the extracellular domain of cytotoxic T-lymphocyte antigen 4 (CTLA-4) linked to a modified Fc of human IgG1. Abatacept binds to CD80 or CD86 and inhibits T-cell activations. Abatacept is moderately effective for PsA, particularly peripheral arthritis, but not for PsO. Abatacept treatment resulted in a significantly higher proportion of patients achieving an ACR20 response at week 24 versus placebo (39.4% vs. 22.3%), resolution of the enthesitis (32.9% vs. 21.2%) and dactylitis resolutions (44.3% vs 34.0%) [69,70]. Abatacept may be employed in case of inadequate response to previous DMARDs if additional systemic therapy for skin lesions is not required.
B7-H3-targeted CAR-T cell therapy for solid tumors
Published in International Reviews of Immunology, 2022
Guangfei Li, Haopeng Wang, Haitao Wu, Jian Chen
Several studies determined that the transmembrane domain that anchors CAR into the lipid membrane also influences CAR expression, stability, synapse formation, and signal transduction, thus affecting CAR-T function ultimately [52–54]. Generally derived from the natural protein CD8α or CD28, the transmembrane domain has not been clearly characterized yet. CD3ζ transmembrane domain was used to generate CARs initially and could incorporate exogenous CARs into endogenous TCRs, but has been rarely applied nowadays due to the impairment in CAR stability [55]. When compared to CAR-Ts generated using the CD8α transmembrane, CAR-Ts incorporating the CD28 transmembrane have superior basal activation levels and secreted more cytokines by engaging endogenous CD28 and forming heterodimers [56,57]. This might be the mechanism to help them to form more efficient immunologic synapses and recognize antigen-low targets [58]. Taken together, the selection of the transmembrane domain for a CAR construct should be based on the requirement of the activation level and the antigen density of the target of interest.
Related Knowledge Centers
- Cd80
- Cd86
- Interleukin
- Interleukin 6
- Protein
- T Cell
- Co-Stimulation
- T-Cell Receptor
- Toll-Like Receptor
- Antigen-Presenting Cell