DataSheet_1_Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia.docx

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

T细胞与B细胞亚群在原始、效应和记忆T细胞成熟过程中的相互作用对于维持免疫反应的平衡至关重要。由X连锁无γ球蛋白血症（XLA）引起的原发性B细胞免疫缺陷为探索B细胞对T细胞亚群的影响提供了一个模型，这一过程始于胸腺选择。在本研究中，我们调查了XLA患者中原始和效应T细胞亚群的特征，揭示了相应的T细胞受体（TCR）库中显著的改变。我们观察到XLA供体中原始CD4+和CD8+ TCR库的多样性降低，表现为免疫衰老。最显著的改变发生在原始CD4+亚群中，我们对这些亚群进行了更深入的探究。特别是，克隆性增加和趋同现象，以及更短的CDR3区域，表明在缺乏B细胞（通常呈递多样性的自身和共生抗原）的情况下，胸腺来源的原始Treg（CD4+CD45RA+CD27+CD25+）的抗原特异性成熟更加集中于狭窄的焦点。XLA患者中原始CD4 T细胞中的Treg比例降低，支持了胸腺原始Treg选择受损的观点。此外，原始Treg亚群在转录组水平上表现出显著差异，包括抗原呈递和髓系细胞特异性基因表达的增加。总之，我们的研究结果表明B细胞在CD4 T细胞亚群的成熟中发挥着积极作用，包括B细胞依赖性的原始Treg TCR库的扩增，这有助于更好地控制自身反应性T细胞。