Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia

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 T_reg (CD4⁺CD45RA⁺CD27⁺CD25⁺) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve T_reg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve T_reg selection. Furthermore, the naïve T_reg 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.