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

ABSTRACT: Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission, and we showed that the 127-hi cell population is a mix of Th1- and Th2-type cells, with a significant bias toward antiinflammatory Th2-type cells. In addition, we extended these findings to show that patients with the highest frequency of 127-hi cells at diagnosis were significantly more likely to maintain ? cell function. Moreover, in patients treated with alefacept in the T1DAL clinical trial, the probability of responding favorably to the antiinflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an antiinflammatory environment that is permissive for partial remission, ? cell survival, and response to antiinflammatory immunotherapy.

SUBMITTER: Narsale A

PROVIDER: S-EPMC7934872 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Narsale Aditi A Lam Breanna B Moya Rosa R Lu TingTing T Mandelli Alessandra A Gotuzzo Irene I Pessina Benedetta B Giamporcaro Gianmaria G Geoffrey Rhonda R Buchanan Kerry K Harris Mark M Bergot Anne-Sophie AS Thomas Ranjeny R Hessner Martin J MJ Battaglia Manuela M Serti Elisavet E Davies Joanna D JD

JCI insight 20210125 2

Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis, has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse type 1 diabetes (T1D). In this study, using Cox model multivariate analysis, we validated our previous findings that patients with the highest frequency of CD4+CD25+CD127hi (127-hi) cells at diag ...[more]

PMID: 33301420

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Project description:BACKGROUND:Type 1 diabetes (T1D) is a T-cell mediated autoimmune disease targeting the insulin-producing pancreatic beta cells. Naturally occurring FOXP3(+)CD4(+)CD25(high) regulatory T cells (T(regs)) play an important role in dominant tolerance, suppressing autoreactive CD4(+) effector T cell activity. Previously, in both recent-onset T1D patients and beta cell antibody-positive at-risk individuals, we observed increased apoptosis and decreased function of polyclonal T(regs) in the periphery. Our objective here was to elucidate the genes and signaling pathways triggering apoptosis in T(regs) from T1D subjects. PRINCIPAL FINDINGS:Gene expression profiles of unstimulated T(regs) from recent-onset T1D (n = 12) and healthy control subjects (n = 15) were generated. Statistical analysis was performed using a Bayesian approach that is highly efficient in determining differentially expressed genes with low number of replicate samples in each of the two phenotypic groups. Microarray analysis showed that several cytokine/chemokine receptor genes, HLA genes, GIMAP family genes and cell adhesion genes were downregulated in T(regs) from T1D subjects, relative to control subjects. Several downstream target genes of the AKT and p53 pathways were also upregulated in T1D subjects, relative to controls. Further, expression signatures and increased apoptosis in T(regs) from T1D subjects partially mirrored the response of healthy T(regs) under conditions of IL-2 deprivation. CD4(+) effector T-cells from T1D subjects showed a marked reduction in IL-2 secretion. This could indicate that prior to and during the onset of disease, T(regs) in T1D may be caught up in a relatively deficient cytokine milieu. CONCLUSIONS:In summary, expression signatures in T(regs) from T1D subjects reflect a cellular response that leads to increased sensitivity to apoptosis, partially due to cytokine deprivation. Further characterization of these signaling cascades should enable the detection of genes that can be targeted for restoring T(reg) function in subjects predisposed to T1D.

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

Publications

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

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