Anti-TNF treatment negatively regulates human CD4+ T-cell activation and maturation in vitro, but does not confer an anergic or suppressive phenotype

TY - JOUR

T1 - Anti-TNF treatment negatively regulates human CD4+ T-cell activation and maturation in vitro, but does not confer an anergic or suppressive phenotype

AU - Povoleri, Giovanni A. M.

AU - Lalnunhlimi, Sylvine

AU - Steel, Kathryn J. A.

AU - Agrawal, Shweta

AU - O'Byrne, Aoife

AU - Ridley, Michael

AU - Kordasti, Shahram

AU - Frederiksen, Klaus S.

AU - Roberts, Ceri A.

AU - Taams, Leonie S.

PY - 2020/3

Y1 - 2020/3

N2 - TNF-blockade has shown clear therapeutic value in rheumatoid arthritis and other immune-mediated inflammatory diseases, however its mechanism of action is not fully elucidated. We investigated the effects of TNF-blockade on CD4 + T cell activation, maturation, and proliferation, and assessed whether TNF-inhibitors confer regulatory potential to CD4 + T cells. CyTOF and flow cytometry analysis revealed that in vitro treatment of human CD4 + T cells with the anti-TNF monoclonal antibody adalimumab promoted IL-10 expression in CD4 + T cells, whilst decreasing cellular activation. In line with this, analysis of gene expression profiling datasets of anti-TNF-treated IL-17 or IFN-γ-producing CD4 + T cells revealed changes in multiple pathways associated with cell cycle and proliferation. Kinetics experiments showed that anti-TNF treatment led to delayed, rather than impaired T-cell activation and maturation. Whilst anti-TNF-treated CD4 + T cells displayed some hyporesponsiveness upon restimulation, they did not acquire enhanced capacity to suppress T-cell responses or modulate monocyte phenotype. These cells however displayed a reduced ability to induce IL-6 and IL-8 production by synovial fibroblasts. Together, these data indicate that anti-TNF treatment delays human CD4 + T-cell activation, maturation, and proliferation, and this reduced activation state may impair their ability to activate stromal cells.

AB - TNF-blockade has shown clear therapeutic value in rheumatoid arthritis and other immune-mediated inflammatory diseases, however its mechanism of action is not fully elucidated. We investigated the effects of TNF-blockade on CD4 + T cell activation, maturation, and proliferation, and assessed whether TNF-inhibitors confer regulatory potential to CD4 + T cells. CyTOF and flow cytometry analysis revealed that in vitro treatment of human CD4 + T cells with the anti-TNF monoclonal antibody adalimumab promoted IL-10 expression in CD4 + T cells, whilst decreasing cellular activation. In line with this, analysis of gene expression profiling datasets of anti-TNF-treated IL-17 or IFN-γ-producing CD4 + T cells revealed changes in multiple pathways associated with cell cycle and proliferation. Kinetics experiments showed that anti-TNF treatment led to delayed, rather than impaired T-cell activation and maturation. Whilst anti-TNF-treated CD4 + T cells displayed some hyporesponsiveness upon restimulation, they did not acquire enhanced capacity to suppress T-cell responses or modulate monocyte phenotype. These cells however displayed a reduced ability to induce IL-6 and IL-8 production by synovial fibroblasts. Together, these data indicate that anti-TNF treatment delays human CD4 + T-cell activation, maturation, and proliferation, and this reduced activation state may impair their ability to activate stromal cells.

KW - adalimumab

KW - CD4 T cells

KW - CyTOF

KW - interleukin-10

KW - TNF inhibitor

UR - http://www.scopus.com/inward/record.url?scp=85076115201&partnerID=8YFLogxK

U2 - 10.1002/eji.201948190

DO - 10.1002/eji.201948190

M3 - Article

SN - 0014-2980

VL - 50

SP - 445

EP - 458

JO - European Journal of Immunology

JF - European Journal of Immunology

IS - 3

ER -