Nonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonist

Koh, Kyung Bong; Cao, Yong; Mangos, Steve; Tardi, Nicholas J.; Dande, Ranadheer R.; Lee, Ha Won; Samelko, Beata; Altintas, Mehmet M.; Schmitz, Vincent P.; Lee, Hyun; Mukherjee, Kamalika; Peev, Vasil; Cimbaluk, David; Hahm, Eunsil

doi:10.1172/jci123386

Cited by 22 publications

(18 citation statements)

References 37 publications

(73 reference statements)

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“…Consistent with data that both ICOS and ICOSL mutations in mice and humans display congruent humoral immune defects, binding assays support that ICOS specifically binds to a unique ligand ICOSL . In contrast to ligands for CD28 (CD80 and CD86), whose expression is restricted to antigen‐presenting cells, ICOSL is also expressed on ILCs, and non‐hematopoietic cells . ICOSL is abundantly expressed on naive B cells through BAFF receptor‐dependent non‐canonical NF‐kB signaling .…”

Section: Icos and Icos Ligandsupporting

confidence: 71%

“…Second, the availability of co‐stimulatory ligands may explain some of the distinct functions of ICOS. In addition to antigen‐presenting cells, ICOSL has been found to be inducibly expressed on fibroblasts, endothelial cells, epithelial cells, muscle fibers, and podocytes under inflammatory conditions. Thus, ICOS co‐stimulation can dominate under situations where CD28 ligands are limited such as in inflamed tissues .…”

Section: Icos and Icos Ligandmentioning

confidence: 99%

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Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

Panneton

Chang

Witalis

et al. 2019

Immunological Reviews

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Human patients with homozygous null mutations in the ICOS gene suffer from recurrent infections due to humoral immune defects. Studies on human patients and mouse models have shown that inducible T-cell co-stimulator (ICOS)-deficient individuals cannot form T follicular helper (Tfh) cells, a group of CD4 T cells that migrate into B cell follicles and facilitate germinal center (GC) reactions. ICOS-induced phosphoinositide 3-kinase signaling pathways have been shown to play critical roles in Tfh programming, migration of Tfh cells into the GC, and delivery of T cell help during Tfh-GC B cell conjugation. These processes are also assisted by ICOS-mediated intracellular calcium mobilization and TANK-binding kinase 1 signaling. However, ICOS signaling also has stimulatory roles in T regulatory cells and innate lymphoid cells (ILCs), providing another layer of complexity. In this review, we discuss celltype-specific signaling mechanisms utilized by ICOS in Tfh cells, T regulatory cells, and ILCs. Whenever relevant, we compare the roles and signaling pathways of ICOS and CD28. Understanding ICOS signal transduction mechanisms used by distinct immune subsets at different stages of immune responses or disease progression may help improve vaccination protocols, treat autoimmune diseases, and enhance cancer immunotherapy. K E Y W O R D S calcium, ICOS, phosphoinositide 3-kinase, signal transduction, T follicular helper cell

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Section: Icos and Icos Ligandsupporting

confidence: 71%

Section: Icos and Icos Ligandmentioning

confidence: 99%

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

Panneton

Chang

Witalis

et al. 2019

Immunological Reviews

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“…A recent report shows that ICOSL also binds to α v β 3 integrin, through an RGD motif that is located in the membrane-distal IgV domain of human ICOSL 33 , whereas in the mouse, it is located in the membrane proximal to the IgC domain. This is intriguing, since α v β 3 integrin is a known ligand also of the RGD motif displayed by OPN, and it suggests that α v β 3 integrin may play a role in the complex interaction between ICOSL and OPN, and also in the conformational changes of OPN acting as a scaffold of multiple receptors on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

Osteopontin binds ICOSL promoting tumor metastasis

et al. 2020

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ICOSL/ICOS are costimulatory molecules pertaining to immune checkpoints; their binding transduces signals having anti-tumor activity. Osteopontin (OPN) is here identified as a ligand for ICOSL. OPN binds a different domain from that used by ICOS, and the binding induces a conformational change in OPN, exposing domains that are relevant for its functions. Here we show that in vitro, ICOSL triggering by OPN induces cell migration, while inhibiting anchorage-independent cell growth. The mouse 4T1 breast cancer model confirms these data. In vivo, OPN-triggering of ICOSL increases angiogenesis and tumor metastatization. The findings shed new light on ICOSL function and indicate that another partner beside ICOS may be involved; they also provide a rationale for developing alternative therapeutic approaches targeting this molecular trio.

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“…Further complexity to the regulation of ICOS‐ICOS‐L interactions is added by the recent discovery of two new proteins that can specifically bind ICOS‐L, namely the α5β3 integrin, 68 and osteopontin. 69 These proteins bind ICOS‐L at sites distinct from that of ICOS, and their effect on ICOS‐induced ICOS‐L internalization and signaling deserves further analysis.…”

Section: Discussionmentioning

confidence: 99%

Role of endocytosis and trans-endocytosis in ICOS costimulator-induced downmodulation of the ICOS Ligand

Aragoneses-Fenoll

Montes-Casado

Ojeda

et al. 2021

Journal of Leukocyte Biology

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The interaction between the T-lymphocyte costimulatory molecule ICOS and its ligand (ICOS-L) is needed for efficient immune responses, but expression levels are tightly controlled, as altered expression of ICOS or ICOS-L may lead to immunodeficiency, or favor autoimmune diseases and tumor growth. Using cells of mouse B cell lymphoma (M12.C3) and melanoma (B16), or hamster CHO cells transfected with various forms of mouse ICOS-L, and ICOS + T cell lines, we show that, within minutes, ICOS induces significant downmodulation of surface ICOS-L that is largely mediated by endocytosis and trans-endocytosis. So, after interaction with ICOS + cells, ICOS-L was found inside permeabilized cells, or in cell lysates, with significant transfer of ICOS from ICOS + T cells to ICOS-Lexpressing cells, and simultaneous loss of surface ICOS by the T cells. Data from cells expressing ICOS-L mutants show that conserved, functionally important residues in the cytoplasmic domain of mouse ICOS-L (Arg 300 , Ser 307 and Tyr 308), or removal of ICOS-L cytoplasmic tail have minor effect on its internalization. Internalization was dependent on temperature, and was partially dependent on actin polymerization, the GTPase dynamin, protein kinase C, or the integrity of lipid rafts. In fact, a fraction of ICOS-L was detected in lipid rafts. On the other hand, proteinase inhibitors had negligible effects on early modulation of ICOS-L from the cell surface. Our data add a new mechanism of control of ICOS-L expression to the regulation of ICOSdependent responses.

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Nonimmune cell–derived ICOS ligand functions as a renoprotective αvβ3 integrin–selective antagonist

Abstract: Conflict of interest: EH, YC, and JR are inventors on a patent application (62676070) of inducible costimulator ligand for use as a renal therapeutic. JR is cofounder and stock holder of TRISAQ, a biotech company with multiple products for kidney disease.

Cited by 22 publications

References 37 publications

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

Osteopontin binds ICOSL promoting tumor metastasis

Role of endocytosis and trans-endocytosis in ICOS costimulator-induced downmodulation of the ICOS Ligand

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