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A pilot study showing associations between frequency of CD4(+) memory cell subsets at diagnosis and duration of partial remission in type 1 diabetes.

ABSTRACT: In some patients with type 1 diabetes the dose of insulin required to achieve euglycemia is substantially reduced soon after diagnosis. This partial remission is associated with ?-cell function and good glucose control. The purpose of this study was to assess whether frequencies of CD4(+) T cell subsets in children newly diagnosed with type 1 diabetes are associated with length of partial remission. We found that the frequency of CD4(+) memory cells, activated Treg cells and CD25(+) cells that express a high density of the IL-7 receptor, CD127 (CD127(hi)) are strongly associated with length of partial remission. Prediction of length of remission via Cox regression is significantly enhanced when CD25(+) CD127(hi) cell frequency is combined with either Insulin Dependent Adjusted A1c (IDAA1c), or glycosylated hemoglobin (HbA1c), or C-peptide levels at diagnosis. CD25(+) CD127(hi) cells do not express Foxp3, LAG-3 and CD49b, indicating that they are neither Treg nor Tr1 cells.

SUBMITTER: Moya R

PROVIDER: S-EPMC4902740 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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A pilot study showing associations between frequency of CD4(+) memory cell subsets at diagnosis and duration of partial remission in type 1 diabetes.

Moya Rosita R Robertson Hannah Kathryn HK Payne Dawson D Narsale Aditi A Koziol Jim J Davies Joanna Davida JD

Clinical immunology (Orlando, Fla.) 20160422

In some patients with type 1 diabetes the dose of insulin required to achieve euglycemia is substantially reduced soon after diagnosis. This partial remission is associated with β-cell function and good glucose control. The purpose of this study was to assess whether frequencies of CD4(+) T cell subsets in children newly diagnosed with type 1 diabetes are associated with length of partial remission. We found that the frequency of CD4(+) memory cells, activated Treg cells and CD25(+) cells that e ...[more]

PMID: 27114212

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Project description:Type 1 diabetes (T1D) is a chronic metabolic disease characterized by the autoimmune destruction of β-cells in the pancreatic islets. T1D is preceded by islet-specific inflammation led by several immune cells. Among them, natural killer (NK) cells are emerging as important players in T1D development. Human NK cells are characterized by CD56 and CD16 expression, which allows classifying NK cells into four subsets: 1) CD56dimCD16+ or effector NK cells (NKeff); 2) CD56brightCD16- or regulatory NK cells (NKreg); 3) intermediate CD56brightCD16+ NK cells; and 4) CD56dimCD16- NK cells, whose function is not well determined. Since many studies have shown that T1D progression is associated with changes in various immune cell types, we hypothesize that the kinetics of NK cell subsets in the blood could correlate with different stages of T1D. To that aim, pediatric patients newly diagnosed with T1D were recruited, and peripheral NK cell subsets were analyzed by flow cytometry at several disease checkpoints: disease onset, partial remission (PR), 8 months (for non-remitters), and 12 months of progression. Our results showed that total NK cells and their four subsets are altered at the early stages of T1D. A decrease in the counts and percentage of total NK cells and NKeff cells at the different disease stages was found when compared to controls. These results suggest the extravasation of these cells into the islets at disease onset, which is maintained throughout the follow-up. By contrast, NKreg cells increased during the early stages after T1D onset, and both intermediate NK cells and CD56dimCD16- NK cells diminished at the PR stage, which might reflect the immunoregulatory attempts and could be candidate biomarkers for this stage. Also, CD56dimCD16- NK cells increased during T1D progression. Finally, changes in CD16 expression were identified in the different T1D stages, highlighting a CD16 expression reduction in total NK cells and NKeff cells 1 year after diagnosis. That may reflect a state of exhaustion after multiple cell-to-cell interactions. Altogether, our preliminary data provide a longitudinal picture of peripheral NK cell subpopulations during the different T1D stages, which could be potential candidate biomarkers indicators of disease progression.

Project description:ObjectiveType 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.MethodsWe 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 post-diagnosis and measured CD4+ T-cell proliferation to proinsulin epitopes and HIPs using an optimised bioassay.ResultsWe 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 proinsulin33-63 (full-length C-peptide). Proinsulin33-63-specific responses were associated with HLA-DR3-DQ2 and/or HLA-DR4/DQ8. In children with T1D, proinsulin33-63-specific T-cell proliferation positively associated with concurrent estimated C-peptide and predicted survival in honeymoon.ConclusionCD4+ T-cell proliferative responses to proinsulin-containing autoantigens are common before and immediately after diagnosis of T1D but decline thereafter. Proinsulin33-63-specific CD4+ T-cell response is a novel marker of estimated residual endogenous β-cell function and predicts a better 2-year disease outcome.

Project description:Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7R?-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7R?hi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages.

Dataset Information

A pilot study showing associations between frequency of CD4(+) memory cell subsets at diagnosis and duration of partial remission in type 1 diabetes.

Publications

A pilot study showing associations between frequency of CD4(+) memory cell subsets at diagnosis and duration of partial remission in type 1 diabetes.

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