Differentially activated B cells develop regulatory phenotype and show varying immunosuppressive features: a comparative study

Abstract

Regulatory B lymphocytes (Bregs) are B cells with well-pronounced immunosuppressive properties, allowing them to suppress the activity of effector cells. A broad repertoire of immunosuppressive mechanisms makes Bregs an attractive tool for adoptive cell therapy for diseases associated with excessive activation of immune reactions. Such therapy implies Breg extraction from the patient’s peripheral blood, ex vivo activation and expansion, and further infusion into the patient. At the same time, the utility of Bregs for therapeutic approaches is limited by their small numbers and extremely low survival rate, which is typical for all primary B cell cultures. Therefore, extracting CD19+ cells from the patient’s peripheral blood and specifically activating them ex vivo to make B cells acquire a suppressive phenotype seems to be far more productive. It will allow a much larger number of B cells to be obtained initially, which may significantly increase the likelihood of successful immunosuppression after adoptive Breg transfer. This comparative study focuses on finding ways to efficiently manipulate B cells in vitro to differentiate them into Bregs. We used CD40L, CpG, IL4, IL21, PMA, and ionomycin in various combinations to generate immunosuppressive phenotype in B cells and performed functional assays to test their regulatory capacity. This work shows that treatment of primary B cells using CD40L + CpG + IL21 mix was most effective in terms of induction of functionally active regulatory B lymphocytes with high immunosuppressive capacity ex vivo.

Breg-Mediated Immunoregulation in the Skin

“…Over the past few decades, therapies specifically targeting B cells have proven highly effective in the clinical realm, particularly in the management of autoimmune diseases [ 120 , 121 ]. At the same time, the diverse range of immunosuppressive mechanisms exhibited by Bregs has positioned the adoptive transfer of these regulatory B cells as a promising therapeutic strategy for conditions marked by the overactivation of immune responses [ 78 , 122 ]. Looking forward, the potential of Breg cell therapy emerges as a beacon of hope for the treatment of cutaneous wounds, including the formidable challenge of chronic wounds resistant to current approaches.…”

“…Therefore, NK-mediated inflammatory processes may hinder wound healing, especially in chronic wounds. In the immunosuppressive tumor setting, Bregs have been reported to suppress IFNγ production by NK cells via the production of IL10 [ 76 ] and to abrogate NK cell-mediated cytotoxicity [ 77 , 78 ]. Transcriptome analysis suggests that Bregs may produce several proteins with suppressive effects on NK cell activating receptors and effector mechanisms [ 27 ].…”

Pathogenic role of different phenotypes of immune cells in airway allergic diseases: a study based on Mendelian randomization

“…Different subsets of the same immune cells have different functions, such as T cells, which have the potential to differentiate into CD4+ T cells and CD8+ T cells, and CD4+ T cells can further differentiate into Th1, Th2, Th17, Treg, and other T-helper cell subsets. The mainstream view is that Th2 and Th17 are associated with an increased risk of AAD, while Treg has immunosuppressive effects; in addition, it has been found that the same immune cell subpopulations but different immune phenotypes have inconsistent roles in disease ( 6 ). As research on immune cells continues to deepen, the functional heterogeneity among subsets of the same immune cells has gradually been discovered by researchers; in order to achieve better therapeutic outcomes, people have begun to explore the changes in the roles of immune cells with different immunophenotypes.…”