Ciliogenesis proteins orchestrate vesicular trafficking pathways that regulate immune synapse (IS) assembly in the non-ciliated T-cells. We hypothesized that ciliogenesis-related genes might be disease candidates for common variable immunodeficiency with impaired T-cell function (T-CVID). We identified a heterozygous, predicted pathogenic variant in the ciliogenesis protein CCDC28B present with increased frequency in a large CVID cohort. We show that CCDC28B participates in IS assembly by regulating polarized T-cell antigen receptor (TCR) recycling. This involves the CCDC28B-dependent, FAM21-mediated recruitment of the actin regulator WASH to retromer at early endosomes to promote actin polymerization. The CVID-associated CCDC28B^R25W variant failed to interact with FAM21, leading to impaired synaptic TCR recycling. CVID T cells carrying the ccdc28b 211 C > T allele displayed IS defects mapping to this pathway that were corrected by overexpression of the wild-type allele. These results identify a new disease gene in T-CVID and pinpoint CCDC28B as a new player in IS assembly.

纤毛发生蛋白协调调节非纤毛 T 细胞中免疫突触 (IS) 组装的囊泡运输通路。我们假设纤毛发生相关基因可能是常见变异型免疫缺陷伴 T 细胞功能受损 (T-CVID) 的候选疾病。我们在大型 CVID 队列中发现了纤毛发生蛋白 CCDC28B 的杂合预测致病性变异，其频率增加。我们表明 CCDC28B 通过调节极化 T 细胞抗原受体 (TCR) 循环参与 IS 组装。这涉及 CCDC28B 依赖性、FAM21 介导的肌动蛋白调节剂 WASH 募集到早期核内体的逆转录酶以促进肌动蛋白聚合。CVID相关的CCDC28B ^R25W变体无法与 FAM21 相互作用，导致突触 TCR 循环受损。携带ccdc28b 211 C > T 等位基因的 CVID T 细胞显示映射到该通路的 IS 缺陷，这些缺陷已通过野生型等位基因的过表达得到纠正。这些结果确定了 T-CVID 中的一个新疾病基因，并将 CCDC28B 确定为 IS 组装中的一个新参与者。