Zeitschrift für klinische und zelluläre Immunologie
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ISSN: 2155-9899
ISSN: 2155-9899
Karin M.E. Andersson1 , Eric Malmhäll-Bah1 , Nina Y.Oparina1 , Weiyang Tao1 , Aridaman Pandit2 , Malin C. Erlandsson1,3, Venkataragavan Chandrasekaran1 , Sofia T. Silfverswärd1 , Rille Pullerits1,3,4, Maria I. Bokarewa1,3*
Objective: 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: Whole-genome transcriptomics by RNA sequencing was done in CD4+T cells from 87 RA patients with low, and from 78 RA patients with high disease activity. Treatment outcomes in PBX1hi and PBX1lo groups were compared. PBX1-associated phenotype and biological processes were identified by clustering of the genes differentially expressed in PBX1hiCD4+ cells. PBX1hi 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: PBX1hiCD4+ cells had imprinted features of pluripotency and lacked cytokine production. In active RA, PBX1hi cells were enriched with CD34+ pre-thymic lymphocyte progenitors. PBX1hi patients had better reduction of DAS28 on anti-TNF treatment and low frequency of non-responders compared to PBX1lo (both, p=0.026). In inactive RA, PBX1hi cells were enriched with post-thymic naïve T cells expressing CD62L/SELL and CD31/ PECAM1. Here, PBX1hi patients required less treatment to reach remission compared to PBX1lo patients (p=0.011). In thymus, CD34 and PECAM1 were annotated within PBX1hi 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 enrichment for PBX1 is associated with pluripotent phenotype of CD4+ cells, which favours treatment responses in RA.