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The Journal of Immunology, 2007, 179, 2046-2050
Copyright © 2007 by The American Association of Immunologists, Inc.
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Cutting Edge: Primary B Lymphocytes Preferentially Expand Allogeneic FoxP3+ CD4 T Cells

Xinjian Chen1 and Peter E. Jensen

Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84132. E-mail address: xinjian.chen@path.utah.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Despite the unequivocal role of B lymphocytes as effecter cells in humoral immunity, studies have reported that B cells are tolerogenic. The impact of B cell-mediated tolerance and its underlying mechanisms are incompletely understood. Using primary B cells as APCs and allogeneic CD4 T cells as responder cells in mixed leukocyte reactions, we find that B cells preferentially expand FoxP3+ over FoxP3– CD4 T cells in the absence of exogenous cytokines. The preferential expansion of Foxp3+ T cells is further enhanced by a partial blockade of class II MHC-TCR interaction but diminished by stimulatory anti-CD28 Ab or at high B to T cell ratios. Gamma irradiation of B cells selectively abrogates their ability to expand isolated CD25+ but not CD25– CD4 T cells; exogenous IL-2 supplement can partially restore this function. B cell-expanded CD25+ T cells express high levels of FoxP3 and are highly inhibitory in an Ag-specific manner.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Blymphocytes are referred to as professional APCs because they constitutively express MHC class II (MHC-II)2 molecules with the capacity to efficiently capture and present Ags to CD4 T cells through BCR-mediated mechanisms. The immunological outcome of B cell-mediated Ag presentation has been a subject of debate. Despite the unequivocal role of B cells in humoral immunity, independent studies have reported persuasive evidence that, under various conditions, B cells are tolerogenic rather than immunogenic (1, 2, 3, 4). The reasons for this discrepancy are not clearly understood. B cell-mediated tolerance appears to use both recessive mechanisms involving T cell clonal deletion or anergy as well as dominant mechanisms involving suppressor T cells. Until recently the nature of suppressor T cells in general was not clearly defined. Over the last few years, significant insight has been gained into the biology of naturally occurring regulatory T (nTr) cells. It is now clear that the transcription factor FoxP3 confers the regulatory function of nTr cells and that nTr cells play a critical role in controlling autoimmunity (5, 6). Despite the defining role of FoxP3 in nTr cells, however, the mechanisms governing the differentiation, maintenance, and propagation of nTr cells remain poorly understood. A recent study reports the role of B cells in recruiting nTr to the CNS during experimental autoimmune encephalomyelitis (7). In the current report, we present direct evidence that primary B cells preferentially expand allogeneic FoxP3+ T cells.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 Disclosures
 References
 
C57BL/6J (B6), BALB/c, and MHC-II deficient mice (B6;129S-H2dlAb1-Ea/J) were purchased from The Jackson Laboratory, maintained in the animal facility of the University of Utah (Salt Lake City, UT) following institutional guidelines, and used at 3 to 5 mo of age. B cells and dendritic cells (DCs) were isolated from B6 spleens in a cell suspension of cold Ca2+- and Mg2+-free PBS containing 2 mM EDTA and 0.5% BSA by positive selection using CD19 or CD11c microbeads (Miltenyi Biotec). Collagenase (1.6 mg/ml) and 0.1% DNase were used to prepare spleen cell suspension for DC isolation. Total CD4 T cells were isolated by depleting lineage-positive cells with CD19, CD11c, CD11b, CD8, and DX-5 (NK) beads. Anti-CD25-biotin and -streptavidin beads were included in the above-mentioned bead mixture to isolate CD25– T cells. CD25+ T cells were isolated by positive selection. For MLR, responder T cells were labeled with 10 µM CFSE and cultured at 1 x 105 cells/well plus 1 x 104 DCs or various number of B cells as indicated in the results. The APCs were either irradiated (2000 rad) or not irradiated as indicated. The culture medium was made of MEM{alpha} plus GlutaMAX MEM (Invitrogen Life Technologies) supplemented with 50 µM 2-ME, HEPES, pyruvate, nonessential amino acids, penicillin/streptavidin, and 10% FCS. Stimulatory anti-CD28 Ab was purchase from BD Biosciences, and the Y-3P mAb was described previously (8). The culture time ranged from 4 to 10 days as indicated. In the inhibition experiments, purified BALB/c CD25+ T cells were expanded with primary B6 B cells for 8 days in the absence of exogenous cytokines, harvested from the culture using Ficoll-Paque followed by the depletion of B cells, and added to the culture at the indicated regulatory T cell (Treg) to CD25– responder T cell ratio. CD4 allophycocyanin, CD25 FITC or PerCP, and B220 PerCP Abs were purchased from BD Bioscience and anti-FoxP3 PE was purchased from eBioscience. The specimens were read on a FACSCalibur flow cytometer using CellQuest and analyzed with FlowJo software. Cells displayed in Figs. 1–5 were gated on a live CD4 T cell gate and results are representative of three or more experiments.


Figure 1
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  		FIGURE 1. CFSE-labeled BALB/c CD4 T cells (a) were cultured with B6 DCs (b) at a DC to T cell ratio of 1:10, or with B6 B cells (c) at 1:1 ratio for 5 days. The displayed cells were gated on live CD4+ cells.

 

Figure 2
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  		FIGURE 2. MLR consisting of B6 B cells (BC) with purified BALB/c CD25– (b) or CD25+ (c and d) T cells (TC). a–c, Culture on day 6; d, culture on day 9.

 

Figure 3
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  		FIGURE 3. MLRs consisting of irradiated (irrad.) B6 B cells (BC) with BALB/c CD25+ T cells (TC) (day 8) (a), CD25– T cells (b), total (tot.) CD4 T cells (c), and CD25+ T cells (d) in the presence of 100 U of IL-2 (all on day 6).

 

Figure 4
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  		FIGURE 4. MLRs consisting of B6 B cells (B) and BALB/c CD4 T cells (T) at different B to T cell ratios: 2:1 (left), 1:1 (middle), and 1:2 (right).

 

Figure 5
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  		FIGURE 5. MLRs consisting of B6 B cells (BC) and BALB/c CD4 T cells (TC) only (left) or supplemented with anti-CD28 Ab (middle) or anti-MHC-II Ab Y-3P (right).

 

   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Early studies showed that priming with DC-depleted allogeneic splenocytes induced specific unresponsiveness to the donor MHC-II determinants (9). To test the possibility that B cells may induce allogeneic tolerance by promoting nTr cell generation, MLRs were performed using CFSE-labeled BALB/c (H-2d) CD4 T cells as responder cells and nonirradiated C57BL/6 (H-2b) B cells or splenic DCs as APCs. No cytokines were added to the culture. T cell proliferation was determined by flow cytometry at days 4–6. Each type of APC induced proliferation of both FoxP3– and FoxP3+ CD4 T cells in the MLRs (Fig. 1), with the overall T cell responses being faster and stronger with DCs compared with B cells. However, a relatively higher percentage of Foxp3+ T cells was obtained in the MLRs with B cells. Primary BALB/c spleen CD4 T cells contained 8–15% of FoxP3+ T cells (Fig. 1a). After culture with B6 B cells, this percentage was increased to 31- 47% in independent experiments, giving rise to a ratio of divided FoxP3+ to FoxP3– T cells approaching or >1 (Fig. 1c), whereas this ratio was 0.08–0.19 with DCs as APCs (Fig. 1b). These results indicate that although they are less potent than DCs in allostimulation, primary B cells preferentially induced the generation of allogeneic FoxP3+ T cells.

To determine whether the increased percentage of FoxP3+ T cells in the MLRs resulted from an isolated expansion of the existing FoxP3+ cells, a conversion of FoxP3– to FoxP3+ cells, or a combination of both, MLRs were performed with sorted CD25– or CD25+ CD4 T cells, again in the absence of exogenous cytokines. Culturing CD25– BALB/c CD4 T cells (Fig. 2a) with B6 B cells resulted in a vigorous expansion of FoxP3– T cells with the appearance of few FoxP3+ cells (Fig. 2b). By contrast, culture of purified CD25+ T cells with B6 B cells resulted in a robust proliferation of T cells that maintained high levels of FoxP3 expression (Fig. 2, c and d). Although the origin of the few FoxP3+ cells that appeared in the culture of purified CD25– T cells remains to be determined, these results suggest that the abundant generation of the FoxP3+ T cells in the MLR with total CD4 T cells results primarily from the expansion of pre-existing FoxP3+ cells (Fig. 1c). Compared with CD25– T cells, the proliferation of isolated CD25+ T cells was slow, lagging behind by 2 to 3 days (Fig. 2, c and d). More B cells were required as APCs to stimulate isolated CD25+ T cells to proliferate compared with CD25– T cells. At a 1:1 B to T cell ratio, B cells induced a vigorous proliferation of purified CD25– T cells (Fig. 2b) but negligible proliferation of purified CD25+ T cells (not shown). At a B to T cell ratio of 4:1, however, robust proliferation of isolated CD25+ T cells could be obtained (Fig. 2, c and d). These findings are consistent with the observation that FoxP3+ T cells are hyporesponsive as compared with Foxp3– T cells (6) but contradict the reports that gamma-irradiated whole splenic APCs, which consist of primarily of B cells, are unable to expand isolated allogeneic CD25+ T cells (10).

To examine the impact of gamma irradiation, irradiated and nonirradiated B cells were compared for their ability to stimulate isolated FoxP3+ or FoxP3– T cells, respectively. The irradiated B cells expand isolated allogeneic CD25+ T cells very poorly, even at a B to T cell ratio of 8:1 (Fig. 3a), but maintained most of their ability to expand the CD25– T cells (Fig. 3b). Therefore, irradiation primarily abrogates the ability of B cells to expand isolated FoxP3+ rather than FoxP3– T cells. To better understand the mechanisms, irradiated B6 B cells were used to stimulate unseparated BALB/c CD4 T cells. This led to proliferation of both FoxP3+ and FoxP3– T cells (Fig. 3c), although the overall T cell proliferation was low as compared with cultures containing only isolated CD25– T cells (Fig. 3b). Therefore, the presence of FoxP3– T cells in the culture can in part restore the ability of irradiated B cells to induce FoxP3+ T cells to proliferate, and the expanded FoxP3+ T cells in turn appear to inhibit proliferation of the FoxP3– T cells. These results implicate the participation of Foxp3– T cell-derived cytokines in promoting the growth of FoxP3+ T cells. Because Foxp3– CD4 T cells secrete IL-2 upon activation and Foxp3+ T cells are incapable of IL-2 production but instead depend on paracrine IL-2 for survival (5), we asked whether the addition of exogenous IL-2 could restore the function of irradiated B cells to expand isolated Foxp3+ T cells. Indeed, exogenous IL-2 led to a marked expansion of the FoxP3+ T cells (Fig. 3d). Given the early observations that activated B cells produce IL-2 (11), our results suggest that a lack of IL-2 production by irradiated B cells may play a role in their inability to expand isolated Foxp3+ T cells, providing a possible explanation for the discrepancy between our findings and previous observations (10). Therefore, IL-2 production by activated B cells (11) may contribute to the ability of primary, nonirradiated B cells to expand isolated FoxP3+ T cells.

Knowing that a high B to T cell ratio was required to efficiently expand isolated FoxP3+ T cells, we asked how this ratio would affect the expansion of FoxP3+ T cells when present in an unseparated CD4 T cell population. MLRs were performed using B cells at different B to T cell ratios. At high B to T cell ratios (2:1 or higher), B cells induced a strong total CD4 T cell proliferation (Fig. 4, left; 83%) dominated by Foxp3– T cells, with the ratio of divided FoxP3+ to FoxP3– T cells being 0.44. At low B to T ratios (Fig. 4, middle and right), the overall T cell proliferation became weaker (34%; Fig. 4, right) but dominated by Foxp3+ T cells (ratio of 1.75). Therefore, despite the fact that B cells can preferentially expand Foxp3+ T cells, this preference is diminished at high B to T cell ratios, suggesting that low levels of allostimulation favor the expansion of FoxP3+ T cells when both FoxP3+ and FoxP3– T cells are simultaneously present as responder cells. To further test this possibility, the stimulatory anti-CD28 mAb or the blocking anti-MHC-II mAb Y-3P (8) was added to the MLRs. The anti-CD28 mAb dramatically augmented the T cell proliferation dominated by Foxp3– T cells (Fig. 5, middle; divided Foxp3+ to Foxp3– T cell ratio of 0.058) as compared with the absence of anti-CD28 (Fig. 5, left; ratio of 0.96). In contrast, in the presence of Y-3P mAb the overall MLR was attenuated (Fig. 5, right; ratio of 1.67). The reduction, however, was due to the diminished proliferation of FoxP3– but not of FoxP3+ T cells, because a higher percentage of FoxP3+ cells was generated than in the absence of blocking mAb (Fig. 5, left). Because early studies showed that the Y-3P Ab was highly potent in blocking allogeneic MLRs composed of irradiated splenocytes as APCs (8), we asked whether this mAb used (at a concentration of 15 µg/ml) in our experiments had completely blocked the MHC-II-TCR interaction. MHC-II–/– B6 B cells were used as APCs and no T cell proliferation was detected (data not shown). Together, these results suggest that the Y-3P mAb promotes Foxp3+ T cell generation by weakening rather than eliminating the MHC-II-TCR interaction between the B and T cells.

The high level of FoxP3 expression detected in B cell-expanded CD25+ T cells (Fig. 2, c and d) suggested that the T cells should have a suppressive function. To confirm this possibility, B6 B cell-expanded BALB/c CD25+ T cells were added to MLRs consisting of BALB/c (H-2d) CD25–CD4+ T cells plus spleen DCs of either B6 (H-2b) or B10.A (H-2a) origin. In the absence of the Tregs, both DC populations induced vigorous proliferation of the BALB/c CD25– T cells (Fig. 6, a-1 and a-3). However, in the presence of B cell-expanded Tregs, even at a ratio of one Treg to 10 CD25– T cells the B6 DC-induced proliferation of the CD25– T cells was almost completely abrogated (Fig. 6a-2). The CD25– T cell proliferation induced by B10.A DCs was also inhibited by B6 B cell-expanded Tregs but to a lesser extent (Fig. 6a-4). The degree of inhibition was dependent on the number of the expanded Tregs added to the cultures (Fig. 6b). These results are similar to the previous studies using DC plus IL-2-expanded Tregs (10).


Figure 6
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  		FIGURE 6. a, MLRs consisting of BALB/c CD4 T cells (TC) with B6 DCs (a-1), B6 DCs plus B6 B cell (BC)-expanded BALB/c CD25+ T cells (a- 2), 10.A DCs (a-3), or B10.A DCs plus B6 B cell-expanded BALB/c CD25+ T cells (a-4). The displayed cells were in the CD4+ and Foxp3– gate. b, Proliferation of the Foxp3– T cells in the presence of various numbers of the expanded CD25+ T cells. Each value given in the represents the average of triplets.

 
The data presented in current study demonstrate that primary B cells preferentially expand allogeneic FoxP3+ CD4 T cells. Previous studies report that DCs can efficiently expand isolated allogeneic nTr cells in the presence of exogenous IL-2 (10), but DCs appear to be much more potent in expanding Foxp3– compared with Foxp3+ T cells when both types of T cells are simultaneously present (12). TGF-beta plus IL-10-conditioned DCs show increased predilection to expand allogeneic nTr cells as compared with GM-CSF conditioned DCs, but those DCs nevertheless expand many more FoxP3– than FoxP3+ cells (12). Although it is not yet completely clear what enables B cells to preferentially expand nTr cells, our data suggest that this property is related to the modest stimulatory function of B cells because: 1) B cells are weaker APCs compared with DCs; 2) a high B to T cell ratio or a stimulatory anti-CD28 mAb increases total T cell proliferation but impairs preferential nTr cell expansion; and 3) partial blockade of MHC-II-TCR interaction by anti-MHC-II mAbs enhances the preferential expansion FoxP3+ T cells, a result consistent with an early report that anti-MHC-II Abs, when administered in vivo, convert immunity to tolerance through mechanisms involving suppressor T cells (13). Using OVA-specific TCR transgenic OT-II T cells as responder cells and B cells as APCs, we have also found that low Ag doses enable B cells to preferentially expand FoxP3+ OT-II cells (not shown). Therefore, modest levels of stimulation favor nTr expansion. Although we have not yet determined whether TGF-beta would confer B cells with an ability to convert FoxP3– to Foxp3+ T cells, preliminary data from others suggest this likelihood (5). Taken together, our data implicate a great therapeutic potential of using primary B cells in conjunction with a MHC-II blockade to deliver Ags of interest for the induction of active immune tolerance such as allogeneic transplant tolerance.

Why should primary B cells be endowed with a property to preferentially expand nTr cells? Dominant tolerance may provide a mechanism to reinforce tolerance to self-peptide-MHC-II complexes expressed on B cells without involving the peripheral deletion of T cells. This might be important because B cells express a vast variety of Ab idiotope-derived epitopes that would have a theoretical potential to be recognized by a large fraction of the T cell repertoire. By maintaining tolerance through a nondeletional mechanism, potentially useful T cell clones may be preserved in the repertoire. As B cells are activated, such as in germinal centers, they become potent APCs (14). Because augmented Ag presentation impairs the ability of B cells to preferentially expand Foxp3+ T cells (Figs. 4 and 5), activated B cells might then preferentially stimulate Ag-specific Th2 effecter cells to obtain T cell help. Further studies are needed to determine the function of activated B cells, such as germinal center B cells, to stimulate nTr as opposed to other CD4 T cell subsets.


   Disclosures
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
References
 
The authors have no financial conflict of interest.


   Footnotes
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Address correspondence and reprint requests to Dr. Xinjian Chen, Department of Pathology, University of Utah School of Medicine, 1520 Emma Eccles Jones Building, 30 North 1900 East, Salt Lake City, UT 84132 Back

2 Abbreviations used in this paper: MHC-II, MHC class II; B6, C57BL/6J; DC, dendritic cell; nTr, naturally occurring regulatory T (cell); Treg, regulatory T cell. Back

Received for publication March 28, 2007. Accepted for publication June 11, 2007.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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  7. Mann, M. K., K. Maresz, L. P. Shriver, Y. Tan, B. N. Dittel. 2007. B cell regulation of CD4+CD25+ T regulatory cells and IL-10 via B7 is essential for recovery from experimental autoimmune encephalomyelitis. J. Immunol. 178: 3447-3456. [Abstract/Free Full Text]
  8. Janeway, C. A., P. J. Conrad, Jr, E. A. Lerner, J. Babich, P. Wettstein, D. B. Murphy. 1984. Monoclonal antibodies specific for Ia glycoproteins raised by immunization with activated T cells: possible role of T cell-bound Ia antigens as targets of immunoregulatory T cells. J. Immunol. 132: 662-667. [Abstract]
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  11. Taira, S., M. Matsui, K. Hayakawa, T. Yokoyama, H. Nariuchi. 1987. Interleukin secretion by B cell lines and splenic B cells stimulated with calcium ionophore and phorbol ester. J. Immunol. 139: 2957-2964. [Abstract]
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