Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse

Abstract

IntroductionNaive B cells are poor antigen-presenting cells (APC) for naive T cells. In many systems, they have been dispensable for CD4 ϩ T-cell priming. 1,2 Yet antigen presentation by naive B cells is not an immunologic null event. Animals can be rendered tolerant toward antigens presented by naive B cells. 3 Indeed, evidence suggests that B cells can take part in antigen presentation via major histocompatibility complex (MHC) II molecules 4-7 and might even be required to reach full T-cell effector potential. 8 We have previously shown that naive B cells, despite low efficiency on a per cell basis, when loaded with specific peptide antigen can induce antigen-specific proliferation in naive T cells. 9 However, the biophysics of the underlying T-B contact was very different from bona fide T-cell activation by dendritic cells (DCs). 10 While T-cell contacts to DCs were dynamic and sequential, contacts to B cells were mostly very stable in vitro and in vivo. 9,11 The functional significance of this discrepancy is not clear.Information transfer between T cell and APC during cell-cell interaction is characterized by the formation of a supramolecular assembly of signaling and adhesion molecules termed immunologic synapse (IS). 12 Its exact function is still debated yet it is generally accepted as a T-cell activating structure. 13,14,14 A mature IS presents with a distinguished central part of the supramolecular activation cluster (c-SMAC) enriched in signaling molecules like T-cell receptor (TCR) and MHC, and a peripheral part (p-SMAC) enriched in adhesion molecules. 15 The formation of a mature IS takes between 30 to 60 minutes. 12 Encounters between DCs and T cells in early and late phases of immune responses, however, last only for several minutes. 16,17 This is too short to form a mature IS. In contrast, antigen-specific contacts to naive B cells invariably last several hours. 9 It is unclear whether a mature synapse can form under these circumstances.Based on these arguments, we reasoned that the molecular organization of the IS between T cells and naive B cells might be different from the one found in T-DC pairs. We also wanted to test the potential consequences for the resulting activated CD4 ϩ T cells. To further evaluate the outcome of antigen-specific CD4 ϩ T-cell stimulation by naive B cells, we investigated the molecular structure of the underlying IS and the phenotype of CD4 ϩ T cells after in vitro contact with specific-antigen loaded naive B cells or DCs.We present evidence that stimulation of naive T cells by naive B cells results in formation of a mature IS which is absent in DC-T-cell pairs. In addition, while DC stimulation generates classical effector T cells, naive B-cell-activated T cells show regulatory capacity in vitro and in vivo. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by gue...

Resting B cells expand a CD4+CD25+Foxp3+ Treg population via TGF‐β3

“…We have identified another mechanism by which resting B cells could be involved in maintaining tolerance by expanding CD4 1 CD25 1 Foxp3 1 Treg populations. Recently, Reichardt et al have shown that B cells generate Treg in the presence of specific antigen [36]. Unlike our results, they show that B cell-stimulated T cells do not have enhanced Foxp3 expression but are functionally suppressive.…”

A B-1a cell subset induces Foxp3− T cells with regulatory activity through an IL-10-independent pathway

“…The parallel studies performed by our group demonstrated that the in vivo function of Treg cells generated by different B-cell subsets, including splenic B-2 and Peyer's patch B cells, was to potently suppress immune responses and alleviate asthmatic symptoms. 9,11 Of note, the in vitro suppressive function of Treg-of-B1a cells was greater than that of reported Treg-of-B2 cells (Figure 1d), and the surface molecules that were upregulated on Treg-of-B2 cells were also highly expressed by Treg-of-B1a cells (Figure 3c). Therefore, the possibility that Treg-of-B1a cells might be able to regulate excessive immune response in vivo was of great expectation.…”

“…In the past few years, several in vitro coculture experiments have shown that B cells have the ability to induce the generation of Treg cells and expand Foxp3 1 CD4 1 T cells in the absence of exogenous cytokines. [8][9][10] Antigen-loaded B cells isolated from Peyer's patches have also been shown to have the potential to induce suppressive Treg cells. 11 In the above-mentioned studies, purified splenic CD19 1 or B220 1 B-2 cells were investigated.…”

“…11 In the above-mentioned studies, purified splenic CD19 1 or B220 1 B-2 cells were investigated. 9,[11][12][13] On the other hand, although CD5 1 B-1a cells have been regarded as regulatory B cells, 14 In several in vitro Treg cell induction studies, especially the induction of the IL-10-producing type 1 Treg (Tr1) cell lineage, IL-10 is indispensable. [15][16][17] Tr1 differentiation can be driven by immature or tolerogenic dendritic cells (DCs) through IL-10.…”

Subcellular dynamics of T cell immunological synapses and kinapses in lymph nodes

“…Reorganization of the actin cytoskeleton (2,3), translocation of the microtubule organizing center (4,5), segregation of surface and signaling molecules into central and peripheral regions of the contact zone (cSMAC and pSMAC, respectively) (6, 7), condensation of membrane microdomains (8), and formation of dynamic microclusters (9)(10)(11)(12)(13) contribute to immunological synapse formation and have been proposed to participate in and/or regulate T cell activation. Of note, the topology of the immunological synapse is not unique and may depend on the type of APC, the T cell phenotype, and the strength of stimulation (14)(15)(16). In various experimental conditions, both bull's eye shaped and multifocal synapses have been described (6,7,17,18).…”