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Toll-like receptor-7 activation in CD8+ T cells modulates inflammatory mediators in patients with rheumatoid arthritis

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Abstract

Rheumatoid arthritis (RA) is an autoimmune disorder of unknown etiology with aberrant immunological responses leading to inflammation, swelling and pain of the joints. CD8+ T cells have been known to be one of the major immune modulators in the progression of RA and the presence of toll-like receptors (TLRs) on these cells further accentuate their role in RA. Herein, we report an increased expression of TLR7 in the endosomes of CD8+ T cells of RA patients correlating with disease severity. The stimulation of TLR7 with Imiquimod (IMQ) in these CD8+ T cells drives the signalling cascade via NFkB and pERK activation and hence an increase in the mRNA transcripts of signature cytokines and cytolytic enzymes. However, a parallel synthesis of Tristetraprolin (TTP), an mRNA destabilizing protein prevents the translation of the mRNA transcripts, leading to a rapid degeneration of the target mRNA. We thus report that a direct TLR7 ligation by its agonist increases cytokine transcript signature but not an equivalent protein surge.

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Acknowledgements

The authors are grateful to Dr. N. Brahma, Pradyumna Bal Memorial Hospital, Bhubaneswar, India for his kind help in collecting blood sample from healthy controls. Nitish Swain expresses his gratitude to University Grants Commission for Junior Research Fellowship [Ref No. 420/(CSIR-UGC NET DEC. 2017)]. Archana Tripathy is thankful to Department of Science and Technology for Senior Research Fellowship (Ref No.DST/INSPIRE/03/2014/000394).

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Authors and Affiliations

  1. Disease Biology Laboratory, School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT), Deemed to be University, Bhubaneswar, Odisha, 751024, India

    Nitish Swain, Archana Tripathy & Bhawna Gupta

  2. Department of Rheumatology, Kalinga Institute of Medical Sciences, Bhubaneswar, Odisha, India

    Prasanta Padhan

  3. Laboratory of Immuno-Genomics and Systems Biology, Institute of Life Sciences, Bhubaneswar, Odisha, India

    Sunil K. Raghav

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Contributions

NS, BG, SR designed and conceptualized the work. NS, AT performed the experiments and drafted the work. NS, PP designed the workflow and recorded clinical data. NS, AT, BG drafted the manuscript. NS, BG, AT, PP, SR critically revised and approved the manuscript.

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Correspondence to Bhawna Gupta.

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The study conducted with the human samples were approved by Institutional Ethical Approval Committee, KIIT University and were in accordance to the the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from all the participants in this study. We would also like to confirm that this work has not been published elsewhere and is not under consideration by another journal. All the authors have approved the submission of the manuscript to Rheumatology International.

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Swain, N., Tripathy, A., Padhan, P. et al. Toll-like receptor-7 activation in CD8+ T cells modulates inflammatory mediators in patients with rheumatoid arthritis. Rheumatol Int 42, 1235–1245 (2022). https://doi.org/10.1007/s00296-021-05050-8

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