AUTHOR=Zacca Estefanía R. , Onofrio Luisina I. , Acosta Cristina D. V. , Ferrero Paola V. , Alonso Sergio M. , Ramello María C. , Mussano Eduardo , Onetti Laura , Cadile Isaac I. , Stancich Maria I. , Taboada Bonfanti Maria C. , Montes Carolina L. , Acosta Rodríguez Eva V. , Gruppi Adriana TITLE=PD-L1+ Regulatory B Cells Are Significantly Decreased in Rheumatoid Arthritis Patients and Increase After Successful Treatment JOURNAL=Frontiers in Immunology VOLUME=9 YEAR=2018 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.02241 DOI=10.3389/fimmu.2018.02241 ISSN=1664-3224 ABSTRACT=

Background: B cells play an important role in the development and maintenance of rheumatoid arthritis (RA). Although IL-10–producing B cells represent a major subset of regulatory B cells (Bregs) able to suppress autoimmune and inflammatory responses, recent reports showed that B cell-mediated immune suppression may also occur independent of IL-10. For instance, B cells can modulate T cell immune responses through the expression of regulatory molecules such as PD-L1. So far, PD-L1-expressing B cells have not been analyzed in RA patients.

Objective: To analyze the frequency of PD-L1-expressing B cells in the peripheral blood of RA patients compared to healthy controls (HC) matched for sex and age, their function on T cell response and their changes in response to therapy.

Methods: Fresh peripheral blood B cells from RA patients and HC were characterized by flow cytometry and their functionality assessed in a co-culture system with autologous T cells.

Results: The frequencies of CD19⁺PD-L1⁺ B cells, CD24^hiCD38⁻PD-L1⁺ and CD24^hiCD38^hiPD-L1⁺ B cells were significantly lower in untreated RA patients than in HC. In a follow-up study, the frequencies of PD-L1⁺ B cells (CD19⁺PD-L1⁺ B cells, CD24^hiCD38⁻PD-L1⁺ and CD24^hiCD38^hiPD-L1⁺ B cells) increased significantly after treatment in good responder patients, although the frequency of total CD24^hiCD38^hi B cells decreased. CD19⁺ B cells from untreated RA patients and HC upregulated PD-L1 expression similarly upon stimulation with CpG plus IL-2 and were able to suppress, in vitro, CD8⁺ T cell proliferation and cytokine production in a PD-L1-dependent manner.

Conclusions: Our results show that PD-L1⁺ B cells exhibiting T cell suppressive capacity are significantly decreased in untreated RA patients but increase in response to successful treatment. PD-L1 expression on B cells from RA patients can be modulated in vitro and PD-L1⁺ B cells could thus provide new perspectives for future treatment strategies.