Co-stimulation and T cells as therapeutic targets

Gizinski, Alison M.; Fox, David A.; Sarkar, Sujata

doi:10.1016/j.berh.2009.12.015

Cited by 20 publications

(4 citation statements)

References 74 publications

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“…Our findings predict that treatment regimens which promote an immuno-inhibitory phenotype and/or suppress the switch towards a pro-inflammatory MC phenotype, should down-regulate undesired CD8+ T-cell responses against human HFs. Our data suggest that it deserves to be tested in the two distinct AA mouse models employed here whether blocking OX40L/OX40 (e.g using oxelumab, which was first developed for the treatment of asthma [84] , [127] ) or 4-1BB/4-1BBL interactions [96] , [128] , or antagonizing PAR-2 [129] , [130] affects the development of AA lesions and/or hair regrowth. However, as these signalling molecules are broadly expressed on immunocytes, more specific therapies should be contemplated, including the use of bi-specific antibodies so as to selectively block MCs [120] .…”

Section: Discussionmentioning

confidence: 99%

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Bertolini

Zilio²,

Rossi³

et al. 2014

PLoS ONE

129

130

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Alopecia areata (AA) is a CD8+ T-cell dependent autoimmune disease of the hair follicle (HF) in which the collapse of HF immune privilege (IP) plays a key role. Mast cells (MCs) are crucial immunomodulatory cells implicated in the regulation of T cell-dependent immunity, IP, and hair growth. Therefore, we explored the role of MCs in AA pathogenesis, focusing on MC interactions with CD8+ T-cells in vivo, in both human and mouse skin with AA lesions. Quantitative (immuno-)histomorphometry revealed that the number, degranulation and proliferation of perifollicular MCs are significantly increased in human AA lesions compared to healthy or non-lesional control skin, most prominently in subacute AA. In AA patients, perifollicular MCs showed decreased TGFβ1 and IL-10 but increased tryptase immunoreactivity, suggesting that MCs switch from an immuno-inhibitory to a pro-inflammatory phenotype. This concept was supported by a decreased number of IL-10+ and PD-L1+ MCs, while OX40L+, CD30L+, 4–1BBL+ or ICAM-1+ MCs were increased in AA. Lesional AA-HFs also displayed significantly more peri- and intrafollicular- CD8+ T-cells as well as more physical MC/CD8+ T-cell contacts than healthy or non-lesional human control skin. During the interaction with CD8+ T-cells, AA MCs prominently expressed MHC class I and OX40L, and sometimes 4–1BBL or ICAM-1, suggesting that MC may present autoantigens to CD8+ T-cells and/or co-stimulatory signals. Abnormal MC numbers, activities, and interactions with CD8+ T-cells were also seen in the grafted C3H/HeJ mouse model of AA and in a new humanized mouse model for AA. These phenomenological in vivo data suggest the novel AA pathobiology concept that perifollicular MCs are skewed towards pro-inflammatory activities that facilitate cross-talk with CD8+ T-cells in this disease, thus contributing to triggering HF-IP collapse in AA. If confirmed, MCs and their CD8+ T-cell interactions could become a promising new therapeutic target in the future management of AA.

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Section: Discussionmentioning

confidence: 99%

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Bertolini

Zilio²,

Rossi³

et al. 2014

PLoS ONE

129

130

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“…In recognition of the biological importance of CD28, a number of immunotherapeutics have been designed to target CD28. The most effective of these has been a soluble form of CTLA-4 (CTLA-4-Ig; Abatacept), which has been FDA approved to treat RA and may be useful in suppressing other autoimmune diseases [59] , [60] , [61] . Small molecule mimics of the CTLA-4 ligand-binding site have also been developed [62] , [63] , [64] , [65] , but both these and CTLA4-Ig target the CD80 and CD86 ligands and indiscriminately inhibit both CD28 and CTLA-4 binding and function.…”

Section: Discussionmentioning

confidence: 99%

T Cell Receptor Signaling Can Directly Enhance the Avidity of CD28 Ligand Binding

et al. 2014

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T cell activation takes place in the context of a spatial and kinetic reorganization of cell surface proteins and signaling molecules at the contact site with an antigen presenting cell, termed the immunological synapse. Coordination of the activation, recruitment, and signaling from T cell receptor (TCR) in conjunction with adhesion and costimulatory receptors regulates both the initiation and duration of signaling that is required for T cell activation. The costimulatory receptor, CD28, is an essential signaling molecule that determines the quality and quantity of T cell immune responses. Although the functional consequences of CD28 engagement are well described, the molecular mechanisms that regulate CD28 function are largely unknown. Using a micropipet adhesion frequency assay, we show that TCR signaling enhances the direct binding between CD28 and its ligand, CD80. Although CD28 is expressed as a homodimer, soluble recombinant CD28 can only bind ligand monovalently. Our data suggest that the increase in CD28-CD28 binding is mediated through a change in CD28 valency. Molecular dynamic simulations and in vitro mutagenesis indicate that mutations at the base of the CD28 homodimer interface, distal to the ligand-binding site, can induce a change in the orientation of the dimer that allows for bivalent ligand binding. When expressed in T cells, this mutation allows for high avidity CD28–CD80 interactions without TCR signaling. Molecular dynamic simulations also suggest that wild type CD28 can stably adopt a bivalent conformation. These results support a model whereby inside-out signaling from the TCR can enhance CD28 ligand interactions by inducing a change in the CD28 dimer interface to allow for bivalent ligand binding and ultimately the transduction of CD28 costimulatory signals that are required for T cell activation.

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“…In the accomplishment of this, the discovery of various leukocyte surface molecules and its ligands interaction will lead to the development of new approaches for treatment of various diseases, including inflammatory diseases and cancers. The PD-1/PD-L1 immune checkpoint blockage in cancer therapy [5–7], the interfering CD28 and CD80/CD86 binding with CTLA-4-Ig in the treatment of rheumatoid arthritis [8, 9] and using anti-CTLA-4 monoclonal antibody (mAb) for cancer treatment [5, 6, 10] are the best examples.…”

Section: Introductionmentioning

confidence: 99%

Interaction of CD99 and its ligand upregulates IL-6 and TNF-α upon T cell activation

et al. 2019

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CD99 has been reported to be involved in T cell regulation. CD99 ligand involvement in the regulation of T cell activation has been postulated. In this study, recombinant CD99 proteins were produced and used as a tool for determining the role of CD99 and its ligand interaction. Recombinant CD99 proteins induced the upregulation of IL-6 and TNF-α expression, but not IFN-γ, in anti-CD3 monoclonal antibody activated T cells. The cytokine alteration was not observed in unstimulated T cells indicating the cytokine upregulation required the signal from T cell activation. The upregulation of IL-6 and TNF-α was, in addition, observed in CD3 - mononuclear cell population including monocytes and NK cells. The recombinant CD99 proteins, however, did not affect either CD25, CD69 or MHC class II expression or T cell proliferation, upon T cell activation. The CD99 ligands were demonstrated to be expressed on monocytes, NK cells and dendritic cells, but not on B and T cells. Our results indicated the presence of CD99 ligands on leukocyte surface. Interaction between CD99 and its ligands involves the regulation of cytokine production.

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Co-stimulation and T cells as therapeutic targets

Cited by 20 publications

References 74 publications

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

Abnormal Interactions between Perifollicular Mast Cells and CD8+ T-Cells May Contribute to the Pathogenesis of Alopecia Areata

T Cell Receptor Signaling Can Directly Enhance the Avidity of CD28 Ligand Binding

Interaction of CD99 and its ligand upregulates IL-6 and TNF-α upon T cell activation

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