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APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients

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Cell Stress and Chaperones Aims and scope

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by a chronic relapsing-remitting joint inflammation. Perturbations in the balance between CD4 + T cells producing IL-17 and CD4 + CD25highFoxP3 + Tregs correlate with irreversible bone and cartilage destruction in RA. APL1 is an altered peptide ligand derived from a CD4+ T-cell epitope of human HSP60, an autoantigen expressed in the inflamed synovium, which increases the frequency of CD4 + CD25highFoxP3+ Tregs in peripheral blood mononuclear cells from RA patients. The aim of this study was to evaluate the suppressive capacity of Tregs induced by APL1 on proliferation of effector CD4+ T cells using co-culture experiments. Enhanced Treg-mediated suppression was observed in APL1-treated cultures compared with cells cultured only with media. Subsequent analyses using autologous cross-over experiments showed that the enhanced Treg suppression in APL1-treated cultures could reflect increased suppressive function of Tregs against APL1-responsive T cells. On the other hand, APL1-treatment had a significant effect reducing IL-17 levels produced by effector CD4+ T cells. Hence, this peptide has the ability to increase the frequency of Tregs and their suppressive properties whereas effector T cells produce less IL-17. Thus, we propose that APL1 therapy could help to ameliorate the pathogenic Th17/Treg balance in RA patients.

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Acknowledgments

Dr. Ger Arkesteijn, Dr. Irene Ludwig, and Drs. Charlotte de Wolf are acknowledged for their assistance. Dr. Emmerik Leijten and Dr. Yusimy Reyes are acknowledged for their support in the selection of patients.

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Author notes

  1. Ariana Barberá

    Present address: Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK

Authors and Affiliations

  1. Biomedical Research Department, Center for Genetic Engineering and Biotechnology, P.O. Box 6162, Havana, 11300, Cuba

    Ariana Barberá, Noraylis Lorenzo, Gabriel Padrón & María del Carmen Domínguez

  2. Infectious Diseases and Immunology Department, Faculty of Veterinary Medicine, University of Utrecht, P.O. Box 80165, NL-3508 TD, Utrecht, The Netherlands

    Peter van Kooten, Willem van Eden & Femke Broere

  3. Department of Rheumatology and Clinical and Laboratory of Translational Immunology, University Medical Centrum Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands

    Joel van Roon

  4. Department of Pediatric Immunology and Laboratory of Translational Immunology, University Medical Center Utrecht, PO Box 85500, 3508 GA, Utrecht, The Netherlands

    Wilco de Jager

  5. Institute of Rheumatology, Ave 10 of October, No. 130, Havana, Cuba

    Dinorah Prada & Jorge Gómez

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  1. Ariana Barberá
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Correspondence to María del Carmen Domínguez.

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The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of the paper.

Funding

This work was supported by the Women in Science Program financed by L’Oreal/UNESCO, grants of Dutch Arthritis Association, and the Innovation Oriented Programme Genomics (IOP) and Biomedical Research Department at Center for Genetic Engineering and Biotechnology.

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Barberá, A., Lorenzo, N., van Kooten, P. et al. APL1, an altered peptide ligand derived from human heat-shock protein 60, increases the frequency of Tregs and its suppressive capacity against antigen responding effector CD4 + T cells from rheumatoid arthritis patients. Cell Stress and Chaperones 21, 735–744 (2016). https://doi.org/10.1007/s12192-016-0698-0

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