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The onset of active disease in systemic lupus erythematosus patients is characterised by excessive regulatory CD4+-T-cell differentiation


1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11

 

  1. Department of Medicine I (Nephrology), University of Heidelberg, Germany.
  2. Department of Obstetrics and Gynaecology, University of Heidelberg, Germany.
  3. Department of Medicine I (Nephrology), University of Heidelberg, Germany.
  4. Institute of Medical Biometry and Informatics, University of Heidelberg, Germany.
  5. Department of Medicine V (Haematology, Rheumatology), University of Heidelberg, Germany.
  6. Department of Medicine V (Haematology, Rheumatology), University of Heidelberg, Germany.
  7. Institute of Immunology, University of Heidelberg, Germany.
  8. Department of Dermatology, University of Heidelberg, Germany.
  9. Department of Medicine V (Haematology, Rheumatology), University of Heidelberg, Germany.
  10. Department of Medicine I (Nephrology), University of Heidelberg, Germany.
  11. Department of Obstetrics and Gynaecology, University of Heidelberg, Germany. andrea.steinborn-kroehl@med.uni-heidelberg.de

CER13127
2021 Vol.39, N°2
PI 0279, PF 0288
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PMID: 32573411 [PubMed]

Received: 20/01/2020
Accepted : 07/04/2020
In Press: 04/06/2020
Published: 09/04/2021

Abstract

OBJECTIVES:
An imbalance between CD4+-regulatory T-cells (Tregs) and CD4+-responder T-cells (Tresps) correlates with active disease flares in systemic lupus erythematosus (SLE) patients. Both cell subsets consist of highly proliferating Tregs/Tresps expressing inducible T-cell co-stimulatory molecule (ICOS) and less proliferating ICOS--Tregs/Tresps.
METHODS:
Six-colour-flow-cytometric analysis was used to examine the effect of ICOS+- and ICOS--Treg/Tresp cell differentiation on the composition of the total CD4+-T-helper cell pool with ICOS+- and ICOS--Tregs/Tresps. Functionality of Tregs was examined using suppression assays.
RESULTS:
In 83 healthy volunteers, the ratio of ICOS+-Tregs/ICOS+-Tresps increased significantly with age, while that of ICOS--Tregs/ICOS--Tresps did not change. In 86 SLE patients (SLEDAI <7), disease activity was associated with an age-independently increased ratio of both ICOS+-Tregs/ICOS+-Tresps and ICOS--Tregs/ICOS--Tresps. In these patients, the functional activity of ICOS+-Tregs, but not of ICOS--Tregs, was preserved. In 13 markedly active disease patients (SLEDAI >7), the percentage of both ICOS+-Tregs and ICOS+-Tresps, was strongly increased within total CD4+-T-helper cells. However, the increased ratio of ICOS+-Tregs/ICOS+-Tresps was not maintained in these patients, due to terminal differentiation and accumulation of naïve cells within total ICOS+-Tregs. Despite increased differentiation of both ICOS--Tregs and ICOS--Tresps, the percentage of ICOS--Tregs increased within CD4+-T-helper cells, while that of ICOS--Tresps decreased, resulting in a significantly increased ratio of ICOS--Tregs/ICOS--Tresps independent of age.
CONCLUSIONS:
Our data reveal a crucial role of Treg immune senescence for the occurrence of disease flares in SLE patients, with ICOS+-Treg cells being most affected.

Rheumatology Article