T regulatory lymphocytes in type 1 diabetes: Impaired CD25 expression and IL-2 induced STAT5 phosphorylation in pediatric patients

Paračková, Zuzana; Kayserová, Jana; Dáňová, Klára; Sismova, K.; Dudkova, Eva; Šumnı́k, Zdenĕk; Koloušková, Stanislava; Lebl, Jan; Stechova, Katerina; Šedivá, Anna

doi:10.1080/08916934.2016.1217998

Cited by 17 publications

(10 citation statements)

References 41 publications

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“…2A), with lower IL-2 responders in the naïve Treg subset associating with lower CD25 expression levels. These data support a strong role for CD25 expression level in each individual in determining Treg IL-2 responses in T1D, as shown by others [19, 27, 28] and in children with T1D [25]. By comparison, IL-2 responsiveness in memory Treg was not as well correlated with memory Teff within the same subject (Fig.…”

Section: Resultssupporting

confidence: 88%

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Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Schwedhelm¹,

Thorpe²,

Murray³

et al. 2017

Clinical Immunology

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The IL-2/IL-2R pathway is implicated in type 1 diabetes (T1D). While its role in regulatory T cell (Treg) biology is well characterized, mechanisms that influence IL-2 responses in effector T cells (Teff) are less well understood. We compared IL-2 responses in 95 healthy control and 98 T1D subjects. In T1D, low IL-2 responsiveness was most pronounced in memory Teff. Unlike Treg, CD25 expression did not influence the Teff responses. Reduced IL-2 responses in memory Teff were not rescued by resting, remained lower after activation and proliferation, and were absent in type 2 diabetes. Comparing basal IL-2 responses in resting versus activated cells, memory Teff displayed lower, but more sustained, responses to IL-2 overtime. These results suggest that T1D–associated defects in the Teff compartment are due to intrinsic factors related to activation. Evaluation of both Teff and Treg IL-2R signaling defects in T1D subjects may inform selection of therapies.

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Section: Resultssupporting

confidence: 88%

“…Decreased memory Teff IL-2 responses are consistent with our previous findings using smaller cohorts [15, 16]. Other studies either did not compare Treg and Teff responses in the same subjects [21, 25], or used assays optimized for detecting IL-2 response in Treg driven by limiting amounts of IL-2 [19], or smaller cohorts size [20]. …”

Section: Resultssupporting

confidence: 86%

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Schwedhelm¹,

Thorpe²,

Murray³

et al. 2017

Clinical Immunology

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“…Mouse studies show that a hallmark of diabetes onset is the apoptosis of pancreatic islet T reg cells, alongside decreased CD25 and Bcl‐2 expression, suggesting local IL‐2 deprivation . In some T1D cohorts, patients have decreased IL‐2 production , and diminished CD25 expression within FoxP3 + T reg cells . Long et al .…”

Section: Treg Cell Dysfunction In Human Diseasementioning

confidence: 99%

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Attias

Al-Aubodah

Piccirillo

2019

Clinical and Experimental Immunology

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Summary Regulatory T (Treg) cells represent an essential component of peripheral tolerance. Given their potently immunosuppressive functions that is orchestrated by the lineage‐defining transcription factor forkhead box protein 3 (FoxP3), clinical modulation of these cells in autoimmunity and cancer is a promising therapeutic target. However, recent evidence in mice and humans indicates that Treg cells represent a phenotypically and functionally heterogeneic population. Indeed, both suppressive and non‐suppressive Treg cells exist in human blood that are otherwise indistinguishable from one another using classical Treg cell markers such as CD25 and FoxP3. Moreover, murine Treg cells display a degree of plasticity through which they acquire the trafficking pathways needed to home to tissues containing target effector T (Teff) cells. However, this plasticity can also result in Treg cell lineage instability and acquisition of proinflammatory Teff cell functions. Consequently, these dysfunctional CD4+FoxP3+ T cells in human and mouse may fail to maintain peripheral tolerance and instead support immunopathology. The mechanisms driving human Treg cell dysfunction are largely undefined, and obscured by the scarcity of reliable immunophenotypical markers and the disregard paid to Treg cell antigen‐specificity in functional assays. Here, we review the mechanisms controlling the stability of the FoxP3+ Treg cell lineage phenotype. Particular attention will be paid to the developmental and functional heterogeneity of human Treg cells, and how abrogating these mechanisms can lead to lineage instability and Treg cell dysfunction in diseases like immunodysregulation polyendocrinopathy enteropathy X‐linked (IPEX) syndrome, type 1 diabetes, rheumatoid arthritis and cancer.

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“…On day 7, IFNγ-and IL-17-producing T cells were stained according to a previously published protocol (22). For T regulatory lymphocyte determination, we used a previously published staining protocol (23).…”

Section: T Cell Inductionmentioning

confidence: 99%

Neutrophil Extracellular Trap Induced Dendritic Cell Activation Leads to Th1 Polarization in Type 1 Diabetes

et al. 2020

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Neutrophils releasing neutrophil extracellular traps (NETs) infiltrate the pancreas prior to type 1 diabetes (T1D) onset; however, the precise nature of their contribution to disease remains poorly defined. To examine how NETs affect immune functions in T1D, we investigated NET composition and their effect on dendritic cells (DCs) and T lymphocytes in T1D children. We showed that T1D patient NET composition differs substantially from that of healthy donors and that the presence of T1D-NETs in a mixed peripheral blood mononuclear cell culture caused a strong shift toward IFNγ-producing T lymphocytes, mediated through activation of innate immunity cells in T1D samples. Importantly, in a monocyte-derived DC (moDC) culture, NETs induced cytokine production, phenotypic change and IFNγ-producing T cells only in samples from T1D patients but not in those from healthy donors. RNA-seq analysis revealed that T1D-NETs presence causes TGFβ downregulation and IFNα upregulation and creates pro-T1D signature in healthy moDCs.

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T regulatory lymphocytes in type 1 diabetes: Impaired CD25 expression and IL-2 induced STAT5 phosphorylation in pediatric patients

Cited by 17 publications

References 41 publications

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Mechanisms of human FoxP3+ Treg cell development and function in health and disease

Neutrophil Extracellular Trap Induced Dendritic Cell Activation Leads to Th1 Polarization in Type 1 Diabetes

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