Inducible costimulator (ICOS) potentiates TCR-induced calcium flux by augmenting PLCγ1 activation and actin remodeling

Leconte, Jérémy; Yazdchi, Sahar Bagherzadeh; Panneton, Vincent; Suh, Woong‐Kyung

doi:10.1016/j.molimm.2016.09.022

Cited by 23 publications

(25 citation statements)

References 29 publications

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“…TNF-a is known to be important for the progression of CIA and is involved in human RA (45,46). We previously reported that ICOS can potentiate TCR-mediated intracellular calcium flux (30). In T cells, calcium signaling is known to regulate a wide array of processes ranging from differentiation to effector functions (47).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, there are two more signaling motifs identified in the cytoplasmic tail of ICOS. The second motif, KKKY 170 , in the cytoplasmic tail of ICOS can potentiate intracellular calcium release from the endoplasmic reticulum triggered by TCR engagement (30). The third TNFR-associated factor-like IProx motif links ICOS to TANK-binding kinase 1 and serves as an important mechanism promoting the late stage of Tfh cell differentiation (31).…”

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confidence: 99%

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ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis

Panneton

Yazdchi

Witalis

et al. 2018

The Journal of Immunology

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ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis

Panneton

Yazdchi

Witalis

et al. 2018

The Journal of Immunology

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“…Contrastingly, unlike CD28, it also binds to TBK1 through a TRAF‐like motif involving the TM‐proximal KKKY sequence . However, the molecular mechanisms regulating TM‐proximal function of ICOS are yet to be identified . CD5 is a negative regulator of T cell signaling and contains an ITIM .…”

Section: Electrostatic Interaction‐driven Lipid Bindingmentioning

confidence: 99%

Electrostatic interactions: From immune receptor assembly to signaling

Connolly

Gagnon

2019

Immunological Reviews

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Our ability to mount a long-lasting and protective immune response relies on a variety of immune receptors that enable the recognition of ongoing infections, which triggers the adaptation of a myriad of immune cells. The organization of several immune receptors, such as the T cells receptor and several natural killer cell receptors, utilizes different modules for ligand recognition and signaling. These receptors require specific recognition mechanisms between the different modules in order to ensure proper assembly and function. Once assembled, immune receptors must remain inactive in the absence of ligand to prevent the onset of unwanted immune response.Indeed, several mechanisms exist to prevent aberrant immune receptor signaling in the absence of ligand to avert the initiation of uncontrolled autoimmunity. However, once a ligand is recognized, immune receptors must rapidly and specifically engage kinases to initiate highly regulated signaling cascades that lead to the initiation of transcriptional programs that dictate the immune response. Over the last decade, compelling evidence have been presented which suggest that electrostatic interactions are critical for many aspects of immune receptor functions. In the work that follows, we present an overview of the literature that have provided evidence that illustrate how electrostatic interactions regulate immune receptor assembly, inactive state, triggering, and signaling.

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“…We have shown that mutation of the key Tyr 181 in the SH2‐binding motif (YMFM) in the cytoplasmic tail selectively abrogates PI3K activation without affecting calcium flux in T cells using a knockin mouse line ICOS‐Y181F . We also found that mutations of the membrane‐proximal KKKY motif weaken calcium flux independently of PI3K activation in Jurkat cells or primary CD4 T cells reconstituted with mutant constructs . However, mutation of any one of the three Lys residues into Ala within the KKKY motif reduced the level of ICOS on the cell surface, indicating a dual role of the KKKY motif in stabilizing ICOS surface expression and calcium flux .…”

Section: Icos and Icos Ligandmentioning

confidence: 94%

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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Inducible costimulator (ICOS) potentiates TCR-induced calcium flux by augmenting PLCγ1 activation and actin remodeling

Cited by 23 publications

References 29 publications

ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis

ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis

Electrostatic interactions: From immune receptor assembly to signaling

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

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