Functional STAT3 deficiency compromises the generation of human T follicular helper cells
Date
2012
Authors
Ma, Cindy
Avery, Danielle T
Chan, Anna
Batten, Marcel L
Bustamante, Jacinta
Boisson-Dupuis, Stephanie
Arkwright, Peter D
Kreins, Alexandra Y
Averbuch, Diana
Engelhard, Dan
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American Society of Hematology
Abstract
T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4 + T cells to the Tfh lineage, because IL-12 induces naive human CD4 + T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4 + T cells from patients deficient in IL-12Rp1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4 + T cells. Defective expression of IL-21 by STAT3-deficient CD4 + T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4 +CXCR5 + T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
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Keywords: chemokine receptor CXCR5; interleukin 12; interleukin 12 receptor beta1; interleukin 21; protein bcl 6; protein kinase TYK2; STAT1 protein; STAT3 protein; adolescent; adult; article; B lymphocyte; CD4+ T lymphocyte; cell line; cell lineage; cell maturatio
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Blood
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Journal article
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2037-12-31
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