TY - JOUR
T1 - DRB1*0402 may influence arthritis by promoting naive CD4+ T-cell differentiation in to regulatory T cells
AU - Luckey, David
AU - Behrens, Marshall
AU - Smart, Michele
AU - Luthra, Harvinder
AU - David, Chella S.
AU - Taneja, Veena
N1 - Publisher Copyright:
© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2014/11/1
Y1 - 2014/11/1
N2 - HLA-DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), while HLA-DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4+ T-cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen-specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4+ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN-γ. *0401 Tg mice harbor memory CD4+ T cells that differentiate into IL-17+ cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg-cell numbers in *0401 Tg mice, causes immune dysregulation.
AB - HLA-DRB1*0401 expression in humans has been associated with a predisposition to developing rheumatoid arthritis (RA) and collagen-induced arthritis (CIA), while HLA-DRB1*0402 is not associated with susceptibility. Here, we determined if mice transgenic (Tg) for human *0401 have a CD4+ T-cell repertoire that predetermines proinflammatory cytokine production. The data show that both *0401 and *0402 Tg mice can produce TH1/TH17 cytokines, although the kinetics of response may be different. However, in the context of antigen-specific responses in a CIA model, *0402 Tg mice generate a TH2 response that may explain their resistance to developing arthritis. In addition, a significant subset of naïve CD4+ T cells from *0402 Tg mice can be activated in polarizing conditions to differentiate into Treg cells that produce IFN-γ. *0401 Tg mice harbor memory CD4+ T cells that differentiate into IL-17+ cells in various polarizing conditions. Our data suggest that *0401 Tg mice generate a strong immune response to lipopolysaccharide and may be efficient in clearing infection, and may *0401 have been evolutionarily selected for this ability. Autoimmunity, such as RA, could likely be a bystander effect of the cytokine storm that, along with the presence of low Treg-cell numbers in *0401 Tg mice, causes immune dysregulation.
KW - Humanized mice
KW - Immune dysregulation
KW - Regulatory T cells
KW - Rheumatoid arthritis
KW - T-cell polarization
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U2 - 10.1002/eji.201344424
DO - 10.1002/eji.201344424
M3 - Article
C2 - 25103892
AN - SCOPUS:84916889594
SN - 0014-2980
VL - 44
SP - 3429
EP - 3438
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 11
ER -