Immune Checkpoint Dysfunction Remodels Adaptive Immune Receptor Repertoires in CTLA-4 Insufficiency and LRBA Deficiency.

Abstract

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a critical negative regulator of T-cell activation, and its function is impaired either directly in CTLA-4 insufficiency or indirectly through LRBA deficiency. Although the immunological consequences of these closely related inborn errors of immunity (IEI) have been extensively characterized, their impact on adaptive immune receptor repertoires (AIRRs) remains poorly understood. Here, we performed a comprehensive analysis of αβ T-cell receptor (TCR) and B-cell receptor (BCR) repertoires in patients with CTLA-4 insufficiency and LRBA deficiency using high-resolution AIRR sequencing (AIRR-seq). Total and naïve CD4⁺ and CD8⁺ T-cell subsets were purified from patients with CTLA-4 insufficiency (n = 11), LRBA deficiency (n = 10), and healthy controls (n = 11), followed by sequencing of complete TRA and TRB V(D)J regions. Bulk sequencing of IgM and IgG heavy-chain repertoires was additionally performed in a subset of patients. Both CTLA-4 insufficiency and LRBA deficiency were associated with marked restriction of the αβ TCR repertoire, with the most pronounced abnormalities observed in the CD8⁺ compartment. Notably, repertoire restriction extended into the naïve CD8⁺ T-cell compartment in LRBA-deficient patients. In contrast, the IgM repertoire remained broadly preserved despite enrichment of the autoreactivity-associated IGHV4-34 gene segment, whereas the switched IgG repertoire was significantly restricted. Collectively, these findings demonstrate that inherited disruption of the CTLA-4/LRBA axis profoundly remodels AIRRs, preferentially affecting CD8⁺ T-cell diversity while also constraining humoral immunity, and highlight a central role for this immune checkpoint pathway in maintaining adaptive immune repertoire diversity and clonal homeostasis.