PD-1 deficiency reshapes the TCRβ repertoire and T-cell developmental programs associated with susceptibility to lupus-like autoimmunity.

Introduction: Programmed cell death protein-1 (PD-1) functions as a pivotal immune checkpoint, essential for maintaining peripheral immune tolerance, and serves as a significant therapeutic target in cancer immunotherapy. Nevertheless, the relationship between PD-1 deficiency and baseline alterations in T-cell receptor (TCR) repertoire organization, as well as the susceptibility to lupus-like autoimmunity, remains inadequately elucidated. Methods: In this study, we integrated immune repertoire sequencing with bulk RNA sequencing of peripheral blood mononuclear cells (PBMCs) to delineate the organization of the TCRβ repertoire and genotype-associated transcriptional changes in PD-1-deficient mice. To assess autoimmune susceptibility following an environmental immune challenge, we utilized a Results: Our findings revealed that PD-1-deficient mice exhibited alterations in TCRβ repertoire diversity, complementarity-determining region 3 (CDR3) length distributions, TRBV/TRBJ segment usage, V-D-J recombination patterns, and clonotype abundance. Through transcriptomic analysis, we identified significant alterations in the expression of genes linked to lymphocyte development and the maintenance of the T-cell receptor (TCR) repertoire. Concurrently, our predicted regulatory-network analysis highlighted FOXC1, E2F1, GATA2, and MEF2A as potential upstream transcription factors implicated in subsets of these transcriptional changes. PD-1 deficiency was correlated with modified proportions of T cells, natural killer (NK) cells, B cells, and the CD4 Discussion: Collectively, our findings suggest that PD-1 deficiency is linked to disrupted TCRβ repertoire organization, extensive immune dysregulation, and an increased vulnerability to infection-induced lupus-like autoimmunity.