ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2

Weber, Jan P.; Fuhrmann, Franziska; Feist, Randi K.; Lahmann, Annette; Baz, Maysun S. Al; Gentz, Lea-Jean; Van, Dana Vu; Mages, Hans W.; Haftmann, Claudia; Riedel, René; Grün, Joachim R.; Schuh, Wolfgang; Kroczek, Richard A.; Radbruch, Andreas; Mashreghi, Mir‐Farzin; Hutloff, Andreas

doi:10.1084/jem.20141432

Cited by 252 publications

(327 citation statements)

References 62 publications

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“…The data in this report, however, is in agreement with results seen following NP-OVA immunization of Icos −/− mice or mice treated with anti-ICOSL, in which Bcl6 expression was not altered in T FH cells (53). Additionally, the literature suggests the involvement of other proteins, such as LEF-1 and TCF-1, in priming Bcl6 induction and T FH cell commitment prior to ICOS signaling (66).…”

Section: Discussionsupporting

confidence: 91%

“…Given previous indications regarding the role of ICOS in T FH cell differentiation (42, 43, 53), it was intriguing to observe that T FH cells were not only present in Icos −/− mice, but found at a similar quantity to those in WT mice at day 6 p.i. This suggests that additional signals contribute to T FH cell priming in the absence of ICOS signaling during P. c. chabaudi AS infection.…”

Section: Discussionmentioning

confidence: 91%

“…Given the proposed role of ICOS in this process (42, 43, 53), induction of T FH cells in response to P. c. chabaudi AS infection was analyzed at days 6, 11 and 21 p.i. by flow cytometry.…”

Section: Resultsmentioning

confidence: 99%

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The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection

Wikenheiser

Ghosh

Kennedy

et al. 2016

The Journal of Immunology

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Blood-stage Plasmodium chabaudi chabaudi AS infection requires cell- and antibody-mediated immunity to control acute and persistent infection, respectively. The inducible T cell co-stimulator (ICOS) regulates CD4+ T cell activation and promotes the induction of follicular helper T (TFH) cells—CD4+ T cells that support B cell affinity maturation within germinal centers (GCs), resulting in the production of high-affinity antibodies (Abs). Here, we demonstrate that, in response to P. c. chabaudi AS infection, the absence of ICOS resulted in an enhanced TH1 immune response that reduced peak parasitemia. Despite the absence of ICOS, CD4+ T cells were capable of expressing PD-1, Bcl6, and CXCR5 during early infection, indicating TFH cell development was not impaired. However, by day 21 post-infection, Icos−/− mice accumulated fewer splenic TFH cells compared to Icos+/+ mice, leading to substantially fewer GC B cells and a decrease in affinity, but not production, of parasite-specific isotype-switched Abs. Moreover, treatment of mice with anti-ICOSL Abs to modulate ICOS-ICOSL signaling revealed a requirement for ICOS in TFH cell differentiation only after day 6 post-infection. Ultimately, the quality and quantity of isotype-switched Abs produced in Icos−/− mice declined over time, resulting in impaired control of persistent parasitemia. Collectively, these data suggest ICOS is not required for TFH cell induction during P. c. chabaudi AS infection, or production of isotype-switched Abs, but is necessary for maintenance of a sustained high-affinity, protective Ab response.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 91%

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The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection

Wikenheiser

Ghosh

Kennedy

et al. 2016

The Journal of Immunology

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“…In accordance with a low abundance of KLF2, we found a high abundance of CXCR5 and low expression of S1PR1 in T cells from children with ongoing islet autoimmunity. In addition, ICOS was highlighted to maintain the TFH phenotype by repressing KLF2 (57).…”

Section: Cd4mentioning

confidence: 99%

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

Serr

Fürst

Ott

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)+CD4+ TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) - phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTEN-PI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity.

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“…Fifty-six subjects with SLE were randomised to receive placebo or AMG 557 at 6,18,30,45,70,140 or 210 mg subcutaneously in seven sequential rising-dose cohorts. Subjects were administered AMG 557 or placebo on days 1, 15, 29, 43, 57, 71 and 85.…”

Section: Methodsmentioning

confidence: 99%

Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus

et al. 2016

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ObjectivesTo evaluate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single-dose and multiple-dose administration of AMG 557, a human anti-inducible T cell co-stimulator ligand (ICOSL) monoclonal antibody, in subjects with systemic lupus erythematosus (SLE).MethodsPatients with mild, stable SLE (n=112) were enrolled in two clinical trials to evaluate the effects of single (1.8–210 mg subcutaneous or 18 mg intravenous) and multiple (6 –210 mg subcutaneous every other week (Q2W)×7) doses of AMG 557. Subjects received two 1 mg intradermal injections 28 days apart of keyhole limpet haemocyanin (KLH), a neoantigen, to assess PD effects of AMG 557. Safety, PK, target occupancy, anti-KLH antibody responses, lymphocyte subset analyses and SLE-associated biomarkers and clinical outcomes were assessed.ResultsAMG 557 demonstrated an acceptable safety profile. The PK properties were consistent with an antibody directed against a cell surface target, with non-linear PK observed at lower concentrations and linear PK at higher concentrations. Target occupancy by AMG 557 was dose dependent and reversible, and maximal occupancy was achieved in the setting of this trial. Anti-AMG 557 antibodies were observed, but none were neutralising and without impact on drug levels. A significant reduction in the anti-KLH IgG response was observed with AMG 557 administration without discernible changes in the anti-KLH IgM response or on the overall IgG levels. No discernible changes were seen in lymphocyte subsets or in SLE-related biomarkers and clinical measures.ConclusionsThe selective reduction in anti-KLH IgG demonstrates a PD effect of AMG 557 in subjects with SLE consistent with the biology of the ICOS pathway and supports further studies of AMG 557 as a potential therapeutic for autoimmune diseases.Trial registration numbersNCT02391259 and NCT00774943.

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ICOS maintains the T follicular helper cell phenotype by down-regulating Krüppel-like factor 2

Cited by 252 publications

References 62 publications

The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection

The Costimulatory Molecule ICOS Regulates Host Th1 and Follicular Th Cell Differentiation in Response to Plasmodium chabaudi chabaudi AS Infection

miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity

Inducible T-cell co-stimulator ligand (ICOSL) blockade leads to selective inhibition of anti-KLH IgG responses in subjects with systemic lupus erythematosus

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