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Clin Exp Immunol. 2019 Sep 26. doi: 10.1111/cei.13375. [Epub ahead of print]

In-vivo assessment of T cell kinetics in individuals at risk for type 1 diabetes.

Author information

1
Diabetes Clinical Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
2
Translational Research Program, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.

Abstract

We previously assessed the kinetics of T cell turnover in vivo by labeling cells with 2 H-H2 O over 42 days in individuals with type 1 diabetes (T1D) and demonstrated an increased turnover of CD4 memory T cells. We have now tested T cell turnover in individuals at risk for T1D using a 3-4-day labeling protocol with 2 H-glucose. We studied 30 relatives with T1D with and without autoantibodies, and 10 healthy controls. Peripheral blood mononuclear cells (PBMC) were flow-sorted into T cell subsets of interest; 2 H-DNA enrichment was measured by mass spectrometry and in-vivo turnover was calculated as maximum fractional enrichment of deuterated adenosine (Fmax ). Among CD4+ cells, Fmax was highest in regulatory T cells (Treg ), followed by effector and central memory T cells and lowest in naive cells. Similarly, CD8+ central and effector memory T cells had a higher turnover than CD8+ terminally differentiated effector memory T cells (TEMRA) and CD8+ -naive T cells. Relatives as a group showed significantly increased Treg turnover by Fmax compared to controls (1·733 ± 0·6784% versus 1·062 ± 0·3787%, P = 0·004), suggesting pre-existing immune dysfunction within families with T1D. However, there was no significant difference in Fmax between groups according to autoantibody or glucose tolerance status. Repeat testing in 20 subjects 1 year later demonstrated relatively higher within-subject compared to between-subject variability for the measurement of Fmax in various T cell subsets. The short labeling protocol with 2 H-glucose should be applied in the context of a clinical trial in which the therapy is expected to have large effects on T cell turnover.

KEYWORDS:

Autoantibodies; CD4 T cells; CD8 T cells; Deuterium labeled glucose (heavy glucose); Isotope labeling; Regulatory T cells; T Cell kinetics; Type 1 diabetes

PMID:
31557315
DOI:
10.1111/cei.13375

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