Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission.
OBJECTIVE
Accumulating data support the role of regulatory T cells, a subset of CD4+ T cells that expresses CD25(high) and the transcription factor forkhead box P3 (FoxP3), in controlling and preventing autoimmunity. In Wegener's granulomatosis (WG), an autoimmune vasculitis, up-regulation of CD25 on circulating CD4+ T cells has been observed, even in patients in remission. The objective of this study was to test whether the frequency and/or function of Treg cells from WG patients in remission are disturbed.


METHODS
Peripheral blood mononuclear cells were freshly isolated from 52 WG patients in remission and from 27 age- and sex-matched healthy control subjects. The proportion of circulating Treg cells was assessed by flow cytometry using CD4, CD25, FoxP3, and CD45RO markers. Anergy and suppressive function of CD25(high),CD4+ T cells were determined using polyclonal stimulants and coculture assay in 10 WG patients in remission and in 10 age- and sex-matched healthy controls.


RESULTS
In WG patients, a significant increase was observed in the percentage of circulating CD25(high),CD4+ and CD25(low),CD4+ T cells, whereas CD25-,CD4+ T cells were decreased, as compared with healthy controls. Among circulating CD4+ T cells, an expanded percentage of Treg cells (CD25(high),FoxP3+) with memory phenotype was present in WG patients. However, when the suppressive function of CD25(high),CD4+ T cells was tested, CD25(high),CD4+ T cells from WG patients showed diminished or absent suppression of responder T cell proliferation. The impaired suppression was not due to responder cell resistance (as shown by crisscross experiments with T cells from healthy controls) or altered survival of Treg cells.


CONCLUSIONS
These data indicate that WG patients in remission have an expanded proportion of Treg cells that are functionally defective. This observation may be relevant to the development and relapsing course of this autoimmune vasculitis.
Abdulahad
Wayel H
WH
University Medical Center Groningen, Groningen, The Netherlands.
Stegeman
Coen A
CA
van der Geld
Ymke M
YM
Doornbos-van der Meer
Berber
B
Limburg
Pieter C
PC
Kallenberg
Cees G M
CG
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015551:Autoimmunity / Q000276:immunology; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D049109:Cell Proliferation; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D014890:Granulomatosis with Polyangiitis / Q000276:immunology* / Q000503:physiopathology* / Q000628:therapy; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology* / Q000502:physiology*
D015704:CD4 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007166:Immunosuppressive Agents; D053645:Interleukin-2 Receptor alpha Subunit; D017493:Leukocyte Common Antigens