Transplantation Unit, Renal Division, Department of Medicine, University Health Center of Quebec, Laval University, Québec, QC, Canada.
Department of Pathology, University Health Center of Quebec, Laval University, Québec, QC, Canada.
Sci Rep. 2018 Mar 5;8(1):4025. doi: 10.1038/s41598-018-22391-w.
Follicular helper T cells (Tfh) are crucial for the production of high-affinity antibodies, such as alloantibodies, by providing the signals for B-cell proliferation and differentiation. Here, we demonstrate that human allogeneic dendritic cells (DC) stimulated with antibodies against HLA class II antigens preferentially differentiate human naive CD4 T cells into Tfh cells. Following coculture with DCs treated with these antibodies, CD4 T cells expressed CXCR5, ICOS, IL-21, Bcl-6 and phosphorylated STAT3. Blockade of IL-21 abrogated Bcl-6, while addition of the IL-12p40 subunit to the coculture increased CXCR5, Bcl-6, phosphorylated STAT3 and ICOS, indicating that they were both involved in Tfh polarization. We further phenotyped the peripheral T cells in a cohort of 55 kidney transplant recipients. Patients with anti-HLA-II donor-specific antibodies (DSA) presented higher blood counts of circulating Tfh cells than those with anti-HLA-I DSAs. Moreover, there was a predominance of lymphoid aggregates containing Tfh cells in biopsies from patients with antibody-mediated rejection and anti-HLA-II DSAs. Collectively, these data suggest that alloantibodies against HLA class II specifically promote the differentiation of naive T cells to Tfh cells following contact with DCs, a process that might appear in situ in human allografts and constitutes a therapeutic target.
滤泡辅助 T 细胞（Tfh）对于产生高亲和力抗体（如同种异体抗体）至关重要，它为 B 细胞增殖和分化提供信号。在这里，我们证明，针对 HLA Ⅱ类抗原的抗体刺激的人同种异体树突状细胞（DC）优先将人幼稚 CD4 T 细胞分化为 Tfh 细胞。在用这些抗体处理的 DC 共培养后，CD4 T 细胞表达 CXCR5、ICOS、IL-21、Bcl-6 和磷酸化 STAT3。阻断 IL-21 可消除 Bcl-6，而将 IL-12p40 亚基添加到共培养物中则增加 CXCR5、Bcl-6、磷酸化 STAT3 和 ICOS，表明它们都参与 Tfh 极化。我们进一步对 55 名肾移植受者的外周 T 细胞进行了表型分析。具有抗 HLA-II 同种异体特异性抗体（DSA）的患者的循环 Tfh 细胞计数高于具有抗 HLA-I DSA 的患者。此外，在抗体介导的排斥反应和抗 HLA-II DSA 患者的活检中，存在富含 Tfh 细胞的淋巴聚集物。总之，这些数据表明，针对 HLA Ⅱ类的同种异体抗体在与 DC 接触后，可特异性促进幼稚 T 细胞向 Tfh 细胞分化，这一过程可能在人类同种异体移植物中出现，是一个治疗靶点。
