CD4+CD25+CD127hi cell frequency predicts disease progression in type 1 diabetes

Narsale, Aditi; Lam, Breanna; Moya, R.R. Martínez; Lü, Tingting; Mandelli, Alessandra; Gotuzzo, Irene; Pessina, Benedetta; Giamporcaro, Gian Maria; Geoffrey, Rhonda; Buchanan, Kerry; Harris, Mark; Bergot, Anne‐Sophie; Thomas, Ranjeny; Hessner, Martin J.; Battaglia, Manuela; Serti, Elisavet; Davies, Joanna D.

doi:10.1172/jci.insight.136114

Cited by 18 publications

(17 citation statements)

References 77 publications

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“…Furthermore, mechanisms of immune regulation are non-linear along the natural history of T1D—matching well with the proposed relapsing-remitting character of the disease course—and the PR phase is associated with these immunomodulatory changes ( 15 , 16 ). Consistent with this idea, studies investigating changes in immune parameters have reported that patients with the highest frequency of CD4 + CD25 + CD127 hi lymphocytes at disease onset experience the longest PR ( 17 , 18 ), that increased levels of regulatory T, B, and NK cells can be found during T1D progression (which could reflect attempts at restoring self-tolerance) ( 19 , 20 ), and that the absence of IL-4, TNF-α, IL-10, and IL-13 in sera correlates with the length of the remission period ( 21 ). Interestingly, peripheral antigen-specific regulatory T cells (T REG ) diminish during the honeymoon phase in comparison to the time of diagnosis ( 22 ).…”

Section: Introductionmentioning

confidence: 74%

Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

et al. 2022

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The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and β-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naïve T lymphocytes, regulatory T cells (TREG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-β1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of TREG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.

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Section: Introductionmentioning

confidence: 74%

Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

et al. 2022

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“…For CD8 + T cells, the balance between β‐cell‐specific stem cell memory and exhaustion contributes to the rate of disease progression and may be skewed towards exhaustion by immunotherapies such as teplizumab. For CD4 + T cells, the frequency of peripheral blood (PB) T helper 2‐like CD25 + CD127 hi T cells was recently associated with improved β‐cell function 10 . Favorable responses to agents such as Alefacept are also seen in individuals with a higher frequency of CD25 + CD127 hi T cells, suggesting that CD127 hi cells maintain an anti‐inflammatory environment that supports improved β‐cell function and response to immunotherapy 10 …”

Section: Introductionmentioning

confidence: 99%

“…For CD4 + T cells, the frequency of peripheral blood (PB) T helper 2‐like CD25 + CD127 hi T cells was recently associated with improved β‐cell function 10 . Favorable responses to agents such as Alefacept are also seen in individuals with a higher frequency of CD25 + CD127 hi T cells, suggesting that CD127 hi cells maintain an anti‐inflammatory environment that supports improved β‐cell function and response to immunotherapy 10 …”

Section: Introductionmentioning

confidence: 99%

Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

et al. 2021

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Objective. Type 1 diabetes (T1D) is an autoimmune disorder in which autoreactive T cells destroy insulin-producing β-cells. Interventions that preserve β-cell function represent a fundamental therapeutic goal in T1D and biomarkers that predict and monitor β-cell function, and changes in islet autoantigenic signatures are needed. As proinsulin and neoantigens derived from proinsulin peptides (hybrid insulin peptides, HIPs) are important T1D autoantigens, we analysed peripheral blood CD4 + T-cell autoantigen-specific proliferative responses and their relationship to estimated β-cell function. Methods. We recruited 72 people with and 42 without T1D, including 17 pre-diabetic islet antibody-positive and 9 antibody-negative first-degree relatives and 16 unrelated healthy controls with T1D-risk HLA types. We estimated C-peptide level at 3-month intervals for 2 years postdiagnosis and measured CD4 + T-cell proliferation to proinsulin epitopes and HIPs using an optimised bioassay. Results. We show that CD4 + T-cell proliferation to any islet peptide and to multiple epitopes were significantly more frequent in pre-diabetic islet antibody-positive siblings and participants with T1D ≤ 3 months of duration, than in participants with T1D > 3 months or healthy controls. Among participants with T1D and first-degree relatives, CD4 + T-cell proliferation occurred most frequently in response to proinsulin 33-63 (full-length C-peptide). Proinsulin 33-63 -specific responses were associated with HLA-DR3-DQ2 and/or HLA-DR4/ DQ8. In children with T1D, proinsulin 33-63 -specific T-cell proliferation positively associated with concurrent estimated Cpeptide and predicted survival in honeymoon. Conclusion. CD4 + Tcell proliferative responses to proinsulin-containing autoantigens are common before and immediately after diagnosis of T1D but decline thereafter. Proinsulin 33-63 -specific CD4 + T-cell response is a novel marker of estimated residual endogenous β-cell function and predicts a better 2-year disease outcome.

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“…Additionally, we detected a significant increase in CD4 + CD127 hi CD25 + T cells in the DNP group, a population demonstrated to be principally anti-inflammatory and whose frequency is positively correlated with the length of post-T1D diagnosis remission in a young population ( Moya et al., 2016 ; Narsale et al., 2018 , 2020 ). The function of this population in older patients, and its association with macrovascular complications such as DNP in later life, appears worthy of further investigation.…”

Section: Discussionmentioning

confidence: 81%

T lymphocyte and monocyte subsets are dysregulated in type 1 diabetes patients with peripheral neuropathic pain

O’Brien

McGuire

Shinko

et al. 2021

Brain, Behavior, & Immunity - Health

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Diabetic neuropathic pain is a common and devastating complication of type 1 diabetes, but the mechanism by which it develops and persists is yet to be fully elucidated. This study utilised high-dimensional suspension mass cytometry in a pilot cohort to investigate differences in peripheral blood immunophenotypes between type 1 diabetes patients with (n = 9) and without (n = 9) peripheral neuropathic pain. The abundance and activation of several leukocyte subsets were investigated with unsupervised clustering approaches FlowSOM and SPADE, as well as by manual gating. Major findings included a proportional increase in CD4 + central memory T cells and an absolute increase in classical monocytes, non-classical monocytes, and mature natural killer cells in type 1 diabetes patients with pain compared to those without pain. The expression of CD27, CD127, and CD39 was upregulated on select T cell populations, and the phosphorylated form of pro-inflammatory transcription factor MK2 was upregulated across most populations. These results provide evidence that distinct immunological signatures are associated with painful neuropathy in type 1 diabetes patients. Further research may link these changes to mechanisms by which pain in type 1 diabetes is initiated and maintained, paving the way for much needed targeted treatments.

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CD4+CD25+CD127hi cell frequency predicts disease progression in type 1 diabetes

Cited by 18 publications

References 77 publications

Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

Candidate Biomarkers for the Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

Proinsulin‐specific T‐cell responses correlate with estimated c‐peptide and predict partial remission duration in type 1 diabetes

T lymphocyte and monocyte subsets are dysregulated in type 1 diabetes patients with peripheral neuropathic pain

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