Functional STAT3 deficiency compromises the generation of human T follicular helper cells
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-12Rbeta1, 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.
|Authors||Ma, C. S.; Avery, D. T.; Chan, A.; Batten, M.; Bustamante, J.; Boisson-Dupuis, S.; Arkwright, P. D.; Kreins, A. Y.; Averbuch, D.; Engelhard, D.; Magdorf, K.; Kilic, S. S.; Minegishi, Y.; Nonoyama, S.; French, M. A.; Choo, S.; Smart, J. M.; Peake, J.; Wong, M.; Gray, P.; Cook, M. C.; Fulcher, D. A.; Casanova, J. L.; Deenick, E. K.; Tangye, S. G.|
|Responsible Garvan Author|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/pubmed/22403255|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11208|