Background/Purpose: Self-renewal ability, which is important for the adaptive immunity and adequate T cell function, is severely impaired in rheumatoid arthritis (RA). This leads to a disbalance between the increased frequency of common lymphoid progenitors and the low numbers of recent thymic emigrants. We study molecular mechanisms behind T cell reconstitution in rheumatoid arthritis (RA) by asking if PBX1, a transcription factor that maintains stem cell pluripotency, predicts antirheumatic treatment response.

Methods: Blood CD4⁺T cells of 167 RA patients (87 patients with low, and 78 patients with high disease activity) were subjected to transcriptional analysis by RNAseq (Illumina). Treatment outcomes in PBX1^hi and PBX1^lo groups were compared. The genes differentially expressed (DEG, nominal p< 0.05) between PBX1^hi and PBX1^lo groups were identified (Bioconductor, DESeq2 package, Benjamini-Hochberg correction). PBX1-associated phenotype and biological processes were analyzed by covariance clustering of DEGs. PBX1^hi clusters in thymus were identified by a single cell-based analysis. PBX1 transcriptional targets among DEGs were predicted by the integrative analysis of DNA motif, chromatin immunoprecipitation sequencing and open chromatin data.

Results: PBX1^hiCD4⁺ cells had imprinted features of pluripotency and lacked cytokine production. In active RA, PBX1^hi cells were enriched with CD34⁺ pre-thymic lymphocyte progenitors. PBX1^hi patients had better reduction of DAS28 on anti-TNF treatment and low frequency of non-responders compared to PBX1^lo (both, p=0.026). In inactive RA, PBX1^hi cells were enriched with post-thymic naïve T cells expressing CD62L/SELL and CD31/PECAM1. Here, PBX1^hi patients required less treatment to reach remission compared to PBX1^lo patients (p=0.011). Pathway analysis of the DEGs identified strong enrichment for regulation of transcription (cor.p=10^-23), RNA metabolic processes (cor.p=10^-18) and differentiation (cor.p=10^-7) in PBX1^hi CD4⁺ cells, which corresponds to the known biological properties of PBX1. In thymus, CD34 and PECAM1 were annotated within PBX1^hi clusters. Integrative analysis disclosed that central T cell maturation genes TBX21, PRDM1, BATF3 and KLF1 were transcriptionally dependent on PBX1.

Conclusion: This study shows that PBX1-enriched CD4⁺T cells are favorable for treatment success of RA. PBX1 denotes pre-thymic lymphoid progenitors and recent thymic emigrants. T cell maturation genes were transcriptionally dependent on PBX1, which makes PBX1 a regulator of thymic passage by pluripotent CD4⁺ T cells.

« Back to ACR Convergence 2022

ACR Meeting Abstracts - https://acrabstracts.org/abstract/pluripotency-marker-pbx1-predicts-treatment-effect-in-rheumatoid-arthritis/