Expanding Diversity and Common Goal of Regulatory T and B Cells. I: Origin, Phenotype, Mechanisms

Abstract

Immunosuppressive activity of regulatory T and B cells is critical to limit autoimmunity, excessive inflammation, and pathological immune response to conventional antigens or allergens. Both types of regulatory cells are intensively investigated, however, their development and mechanisms of action are still not completely understood. Both T and B regulatory cells represent highly differentiated populations in terms of phenotypes and origin, however, they use similar mechanisms of action. The most investigated CD4⁺CD25⁺ regulatory T cells are characterized by the expression of Foxp3⁺ transcription factor, which is not sufficient to maintain their lineage stability and suppressive function. Currently, it is considered that specific epigenetic changes are critical for defining regulatory T cell stability in the context of their suppressive function. It is not yet known if similar epigenetic regulation determines development, lineage stability, and function of regulatory B cells. Phenotype diversity, confirmed or hypothetical developmental pathways, multiple mechanisms of action, and role of epigenetic changes in these processes are the subject of this review.

Keywords: Epigenetics; Immunosuppression; Regulatory B cell; Regulatory T cell.

Fig. 1

Regulatory T cell development (Churlaud et al. ; Josefowicz and Rudensky ; Kosten and Rustemeyer ; Zhang et al. 2014). Thymus-derived regulatory T cells (tTregs) can develop from SP CD4⁺CD8⁻ thymocytes (a), or an alternative pathway of their development from DN is hypothesized (b); CD8⁺CD25⁺Foxp3⁺ Tregs can also arise in the thymus from SP CD8⁺CD4⁻ thymocytes (c). Both thymic Tregs migrate to peripheral lymphoid organs as mature T cells exhibiting suppressive potential. Peripherally induced Tregs differentiate from antigen-activated naive Th CD4⁺ cells into pTregs of CD4⁺CD25⁺Foxp3⁺ phenotype. Additionally, Tr1 and Th3 are generated (d); naive T CD8⁺ cells can differentiate into CD8⁺CD28⁻ Tregs (e); γδ Tregs can arise from antigen-activated γδ T cells (f). DN double-negative, DP double-positive, SP single-positive, TEC thymic epithelial cells, DC dendritic cells

Fig. 2

Mechanisms of regulatory T cell suppression (Schmidt et al. ; Shevach ; Vignali et al. 2008). Cytokines IL-10, IL-35, and TGF-β can mediate the suppressive activity of tTregs and pTregs by inhibiting cytokine production and proliferation of effector T cells (a); Tregs can exhibit the cytotoxic activity by the mechanisms involving perforin and granzymes release (b); effector T cells can be inhibited through metabolic disruption: high expression of CD25 molecules on Treg cells leads to efficient binding of IL-2 and to apoptosis of Teff cells (c.1); CD39 and CD73 ectoenzymes presented on Tregs participate in the formation of extracellular adenosine which binds A_2AR on the effector T cells leading to their suppression (c.2); inhibition of effector T cells can be mediated by cAMP (c.3); Tregs can inhibit the activity of dendritic cells by CTLA-4 and CD80/CD86 ligation, which weakens the costimulatory signal delivered to effector T cell (d.1). The interaction of CTLA-4 with CD80/CD86 induces IDO that catalyzes the conversion of tryptophan to kynurenine and other pro-apoptotic metabolites (d.1a); LAG-3/MHC II interaction induces the suppression of dendritic cells (d.2) Neuropilin-1 prolongs the interaction between Tregs and dendritic cells, resulting in limited access of effector T cells to dendritic cells (d.3); Tregs inhibit B cell maturation by blocking T-helper cells through the downregulation of inducible T cell costimulator (ICOS; e.1); Tregs can inhibit the synthesis of antibodies and Ig class switching (e.2); Tregs can kill B cells by perforin and granzyme B release (e.3)

Fig. 3

B cell development (a) and hypothetical models for the generation of regulatory B cells (b) (DiLillo et al. ; Gray and Gray ; Mizoguchi and Bhan ; Montecino-Rodriguez and Dorshkind 2012). a B cells develop from progenitors derived from hematopoietic stem cells (HSC). B1 B cells develop from B1 progenitors in the fetal liver with little input from bone marrow beyond the perinatal period. B2 B cells arise from B2 progenitors developing into transitional 2 (T2) B cells. Next, T2 B cells differentiate into marginal zone (MZ) and follicular (FO) B cells occurring in the spleen. Weak B cell receptor (BCR) signals drive the differentiation to MZ B cells, while stronger BCR signals support the differentiation to FO B cells. b B cells of each lineage can develop into Bregs mainly IL-10 producing. 1 Marginal zone (MZ) B cells, transitional stage 2 marginal zone (T2-MZ) B cells, and B-1a cells contain natural regulatory B cells ready to produce IL-10 depending on microenvironmental conditions; 2 B10 cells of CD1d⁺CD5⁺ phenotype, mainly spleen-deriving, produce and secrete IL-10 upon LPS, CD40L, and BAFF stimulation. They can also differentiate into memory and/or plasma cells (indicated by dash lines); 3 two types of regulatory B cells producing IL-10 are postulated. “Acquired type” Breg cells are generated from follicular (FO) B cells upon stimulation by self-antigens or through CD40 signaling after CD40L ligation. “Innate type” Breg cells, which differentiate in mesenteric lymph nodes and share the phenotype of marginal zone (MZ) B cells or B-1a cells upon stimulation by BAFF or TLR ligands (LPS, CpG)

Fig. 4

Breg-mediated IL-10-dependent suppression mechanism (Chesneau et al. ; Mauri and Bosma 2012). a Activation of potentially autoreactive T2-MZ B cells by TLR ligands originated from pathogens induces the synthesis of IL-10 (1). These B cells differentiate to fully active IL-10-producing Bregs upon contact with autoreactive CD4⁺ T cell and CD40/CD40L ligation. In this step, the antigen recognition by BCR is necessary (2). IL-10 released by Bregs suppress Th1, Th17 responses, and TNF-α production by monocytes (3). Interactions of Bregs with naïve T cells CD4⁺CD25⁻ involving B7RP-1/ICOS or CD80/CD86 with their ligands CD28/CTLA-4 induce the differentiation into pTregs and Tr1 regulatory cells (4). b IL-10-producing Bregs inhibit the synthesis of IFN-γ by cytotoxic T CD8⁺ cells, and TNF-α by monocytes resulting in the inhibition of anti-tumor responses. Mo monocytes

Fig. 5

Breg-mediated IL-10-independent suppression mechanism(Ray et al. 2015). 1 Direct suppression of pathogenic T cells through IL-35, ICAM-1/LFA, FasL/Fas or PD-L1/PD-1 interactions. 2 Inhibition of the function of dendritic cells by TGF-β. 3 Inhibition of various immune cells functions through the induction of Treg development or modulation of Treg suppressive activity. ICAM-1 intercellular adhesion molecule-1, LFA lymphocyte function-associated antigen, FasL Fas Ligand, PD-L1 programmed death-ligand 1, TGF-β transforming growth factor β, GITRL glucocorticoid-induced TNF receptor ligand