Follicular Helper T Cells in Autoimmunity

Scherm, Martin G.; Ott, Verena B.; Daniel, Carolin

doi:10.1007/s11892-016-0770-2

Cited by 15 publications

(12 citation statements)

References 92 publications

(110 reference statements)

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“…However, involved signaling pathways that regulate the differentiation of human TFH precursors, as well as their contribution in the initiation and progression of human islet autoimmunity, are incompletely understood (22).…”

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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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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“…T follicular helper cell differentiation is a complex process, which is tightly regulated ( 41 ) (Figure 1 ). It begins during naïve CD4 + T cell priming by DCs in the T cell zone of secondary lymphoid tissues and continues through the first cognate T cell:B cell interaction at the T–B junction until Tfh cells differentiate into mature GC Tfh cells when they enter follicles ( 2 , 3 , 42 , 43 ).…”

Section: Tfh Cell Differentiationmentioning

confidence: 99%

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology

et al. 2018

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T follicular helper (Tfh) cells play key role in providing help to B cells during germinal center (GC) reactions. Generation of protective antibodies against various infections is an important aspect of Tfh-mediated immune responses and the dysregulation of Tfh cell responses has been implicated in various autoimmune disorders, inflammation, and malignancy. Thus, their differentiation and maintenance must be closely regulated to ensure appropriate help to B cells. The generation and function of Tfh cells is regulated by multiple checkpoints including their early priming stage in T zones and throughout the effector stage of differentiation in GCs. Signaling pathways activated downstream of cytokine and costimulatory receptors as well as consequent activation of subset-specific transcriptional factors are essential steps for Tfh cell generation. Thus, understanding the mechanisms underlying Tfh cell-mediated immunity and pathology will bring into spotlight potential targets for novel therapies. In this review, we discuss the recent findings related to the molecular mechanisms of Tfh cell differentiation and their role in normal immune responses and antibody-mediated diseases.

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“…1). TFH cells, which are a subset of CD4 + T cells, provide help to B cells to produce highaffinity antibodies, making them crucial contributors to humoral immunity [102][103][104]. This important role for antibody production suggests TFH precursors as an important effector T cell subset in autoimmunity.…”

Section: Mir-92amentioning

confidence: 99%

miRNA Regulation of T Cells in Islet Autoimmunity and Type 1 Diabetes

Scherm

Daniel

2020

Curr Diab Rep

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Purpose of Review Regulatory T cells (Tregs) are critical contributors to immune homeostasis and their dysregulation can lead to the loss of immune tolerance and autoimmune diseases like type 1 diabetes (T1D). Recent studies have highlighted microRNAs (miRNAs) as important regulators of the immune system, by fine-tuning relevant genes in various immune cell types. In this review article, we discuss recent insights into miRNA regulation of immune tolerance and activation. Specifically, we discuss how the dysregulation of miRNAs in T cells contributes to their aberrant function and the onset of islet autoimmunity, as well as their potential as targets of novel intervention strategies to interfere with autoimmune activation. Recent Findings Several studies have shown that the dysregulation of individual miRNAs in T cells can contribute to impaired immune tolerance, contributing to onset and progression of islet autoimmunity. Importantly, the targeting of these miRNAs, including miR-92a, miR-142-3p and miR-181a, resulted in relevant effects on downstream pathways, improved Treg function and reduced islet autoimmunity in murine models. Summary miRNAs are critical regulators of immune homeostasis and the dysregulation of individual miRNAs in T cells contributes to aberrant T cell function and autoimmunity. The specific targeting of individual miRNAs could improve Treg homeostasis and therefore limit overshooting T cell activation and islet autoimmunity.

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Follicular Helper T Cells in Autoimmunity

Cited by 15 publications

References 92 publications

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

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

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology

miRNA Regulation of T Cells in Islet Autoimmunity and Type 1 Diabetes

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