Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFbeta gene variants.
BACKGROUND
CD4+CD25+ regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females.


RESULTS
To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4+CD25+CD45RO+ T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161, P < 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121, P < 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction of bona fide FOXP3+CD4+CD25+ Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants of CTLA4 and TGFbeta were associated with the decreased frequency of Treg in PBMC, while FOXP3 gene variants were associated with affection status, but not with Treg frequency.


CONCLUSIONS
SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3+CD25- into FOXP3+CD25+ T cells. Treg frequency is highly heritable within SLE families, with specific variants of the CTLA4 and TGFbeta genes contributing to this trait, while FOXP3 contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.
Barreto
Marta
M
Instituto Gulbenkian de Ciência, Rua da Quinta Grande, 6 2780-156 Oeiras, Portugal. mbarreto@igc.gulbenkian.pt
Ferreira
Ricardo C
RC
Lourenço
Lara
L
Moraes-Fontes
Maria F
MF
Santos
Eugénia
E
Alves
Miguel
M
Carvalho
Cláudia
C
Martins
Berta
B
Andreia
Rita
R
Viana
João F
JF
Vasconcelos
Carlos
C
Mota-Vieira
Luísa
L
Ferreira
Carlos
C
Demengeot
Jocelyne
J
Vicente
Astrid M
AM
D000367:Age Factors; D000974:Antibodies, Antinuclear / Q000097:blood; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D017493:Leukocyte Common Antigens; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D008297:Male; D011110:Polymorphism, Genetic; D019655:Quantitative Trait, Heritable; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000276:immunology
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D015704:CD4 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D016212:Transforming Growth Factor beta; D017493:Leukocyte Common Antigens