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The Journal of Immunology, 2005, 175: 21-26.
Copyright © 2005 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: The Link between Lymphocyte Deficiency and Autoimmunity: Roles of Endogenous T and B Lymphocytes in Tolerance1

Birgit Knoechel2, Jens Lohr2, Estelle Kahn and Abul K. Abbas3

Department of Pathology, University of California, San Francisco, CA 94143


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 
We demonstrate that transfer of OVA-specific DO11 CD4+ T cells into mice that lack T and B cells and produce secreted OVA as an endogenous self-protein results in a severe systemic autoimmune reaction with skin inflammation, wasting, and death. The transferred DO11 T cells undergo massive expansion and produce IL-2 and IFN-{gamma} abundantly. Transfer of DO11 cells into OVA-expressing animals in which T cells are absent but B cells are present, leads to mild disease with no death. In this situation, the DO11 cells undergo similar expansion but show poor Th1 differentiation. This regulatory effect of B cells correlates with profound TCR down-regulation. If T cells are present, the DO11 cells fail to expand independent of B cells. These results suggest that both endogenous T and B lymphocytes control T cell tolerance induction and pathogenicity, but at different stages of an anti-self response. Although endogenous T cells prevent expansion and maintain homeostasis, endogenous B cells limit subsequent effector responses of autoreactive CD4+ T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 Disclosures
 References
 
Afundamental feature of the immune system is tolerance to self-Ags. T cell tolerance is maintained by deletion of immature lymphocytes that recognize self-Ags in the generative lymphoid organs, and by anergy, death, and suppression of self-reactive lymphocytes that enter peripheral tissues (1, 2, 3, 4, 5). A question that has not been answered is the nature of the APCs that are important in the induction and maintenance of peripheral tolerance. Candidates include immature dendritic cells and B lymphocytes (6, 7). However, their relative contributions and mechanisms of action are largely matters of speculation (7, 8). It has also been suspected that endogenous polyclonal (i.e., not self-Ag-specific) lymphocytes normally control the activation of self-reactive T cells (9). Clinical immunologists have known that up to 20–25% of patients with various immunodeficiencies develop rheumatoid arthritis and other diseases caused by T cell-mediated autoimmunity (10, 11), and lymphopenia has been described to be a major contributor to autoimmunity in murine models (12) and in graft-vs-host disease (13).

To define the contributions of various lymphocyte subsets to the development of tolerance, we have generated a model in which naive Ag-specific DO11.10 (DO11) CD4+ T cells recognize OVA as a systemically expressed endogenous Ag in the absence of inflammatory stimuli, either in the presence or in the absence of endogenous polyclonal lymphocytes. We show that endogenous CD4+ T lymphocytes and B lymphocytes are both able to control a severe systemic pathologic reaction, however at different levels. These cellular interactions may be essential for strategies to induce tolerance in settings of graft-vs-host disease and autoimmunity.


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

All experimental mice were used at 6–12 wk of age. All mice were age and sex matched (±2 wk). Transgenic mice expressing the DO11.10 TCR (DO11), specific for the chicken OVA peptide (OVA323–339) in the context of the MHC class II molecule I-Ad, were obtained from Dr. K. Murphy (Washington University, St. Louis, MO). All experiments were performed using DO11 cells that had been crossed either onto a Rag1–/– or Rag2–/– background. Soluble OVA transgenic mice (sOVA Tg)4 on a BALB/c background, expressing a soluble form of OVA in the serum under control of the metallothionein promoter I, and PCR typing for OVA expression have been described (our unpublished data and Ref. 14). sOVA Tg mice were bred onto a Rag2–/–, a TCR{alpha}–/– (kindly provided by Dr. R. Locksley, University of California, San Francisco (UCSF)), a JHD–/– (kindly provided by Dr. D. Umetsu, Harvard University, Boston, MA), or crossed onto a JHD–/– x TCR{alpha}–/– background.

All mice were bred and maintained in our pathogen-free facility in accordance with the guidelines of the Laboratory Animal Resource Center of UCSF. All experiments were conducted with the approval of the Committee on Animal Research of UCSF.

Abs and flow cytometry

Splenocytes were stained with the clonotypic Ab KJ1-26 (Caltag Laboratories), anti-CD4 (GK1.5, H129.19, and RM4-5), anti-CD3 (2C11). All Abs were obtained from BD Pharmingen unless otherwise stated. Abs were used as FITC, PE, PE-Cy7, PE-Texas Red, allophycocyanin, or PerCP conjugates. Fc-block (anti-CD16/CD32) was added before staining. Flow cytometric analyses were done on a FACSCalibur with CellQuest Software (both BD Biosciences). For intracellular cytokine stains of IL-2, IFN-{gamma} or, with appropriate isotype controls, DO11 T cells recovered from splenocytes of transfer recipients were restimulated on mitomycin C-treated BALB/c splenocytes for 14 h in the presence of 1 µg/ml OVA peptide. Brefeldin A (Epicenter) was added (10 µg/ml) for the last 2 h of stimulation.

Cell preparations, purifications, and adoptive transfer

CD4+ cells for adoptive transfer were purified from spleen and lymph nodes using Dynabeads according to the manufacturer’s protocol (Dynal). CD4+ purified DO11 Rag–/– cells were adoptively transferred into the indicated recipients by tail vein injection. BALB/c recipients were used as naive controls.

Histology and immunohistochemistry

Tissues were fixed in 10% neutral buffered formalin and embedded in paraffin. Five-micrometer sections were cut and stained with H&E. For immunohistochemistry, tissues were immersed in OCT (TissueTek; Miles), flash frozen, cut into 5-µm sections, and stained with rat anti-CD4-biotin (GK1.5; BD Pharmingen) or biotinylated KJ1-26 and subsequently with streptavidin-HRP (BD Pharmingen). Visualization was done with 3,3'-diaminobenzidine (Sigma-Aldrich).


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
Disclosures
 References
 
Lack of endogenous lymphocytes prevents tolerance to systemic Ag

We have previously shown that naive OVA-specific DO11 T cells, when transferred into sOVA Tg mice that express OVA under the control of the metallothionein promoter, similar to other models of T cell tolerance, undergo an initial proliferation, rapidly expand, and then contract and become functionally unresponsive (14, 15, 16, 17, 18, 19). This model of systemic T cell tolerance allows one to analyze the stimuli and conditions that may cause or abrogate tolerance induction. We chose to study the effects of selective lymphocyte deficiencies, based on the hypothesis that endogenous lymphocytes serve to maintain self-tolerance, and therefore, elimination of endogenous lymphocytes should lead to a loss of tolerance and an autoimmune response.

To test this idea, DO11 Rag–/– cells were transferred into sOVA Tg mice that had been crossed on a Rag–/– background lacking T and B lymphocytes. As previously reported,5 the sOVA Tg Rag–/– transfer recipients develop a wasting syndrome, and in different experiments, ~50% of the mice die within 2 wk (Fig. 1, A and B). No weight loss or lethality is seen in either sOVA Tg wild-type (WT) recipients (lymphocyte-sufficient) or in non-Tg Rag–/– recipients that lack the self-Ag (Fig. 1A, and data not shown). All of the mice show severe ruffling of fur, and swelling of eyes, ears, and paws. Pathologic studies reveal extensive cellular infiltrates in s.c. tissues, most of them staining positive for CD4 (Fig. 1, C and D) and KJ1-26 (data not shown). No infiltration is seen when DO11 Rag–/– cells are transferred into WT sOVA Tg mice. Thus, the severe immune reaction requires both recognition of systemic Ag and the absence of endogenous lymphocytes. Importantly, the recipient mice were not immunized in any way, indicating that recognition of the circulating Ag alone is a sufficient stimulus for the pathologic reaction, and no additional activation is needed to trigger this reaction.



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  		FIGURE 1. Ag recognition in the absence of endogenous B and T cells results in wasting and death. A total of 1 x 106 purified CD4+ DO11 Rag–/– T cells was transferred into sOVA Tg WT, sOVA Tg Rag–/–, or sOVA Tg TCR{alpha}–/– mice on day 0. A, Body weight is depicted as the change in percentage of the starting weight 10 days after T cell transfer. Data are pooled from three experiments (sOVA Tg WT, 4 mice; sOVA Tg Rag–/–, 7 mice; sOVA Tg TCR{alpha}–/–, 9 mice). B, Survival of sOVA Tg Rag–/– in comparison to sOVA Tg TCR{alpha}–/– mice is plotted over time as percentage of surviving mice from three pooled experiments of four (sOVA Tg WT, 4 mice; sOVA Tg Rag–/–, 20 mice; sOVA Tg TCR{alpha}–/–, 12 mice). C, Paraffin sections of skin of the indicated recipients 10 days after T cell transfer were stained with H&E. D, Frozen sections of skin were stained with anti-CD4. One representative section from each group is shown.

 
Absence of endogenous T lymphocytes leads to expansion of Ag-reactive T cells but not their differentiation into effector cells

To examine the role of individual polyclonal lymphocyte subsets in the control of autoimmunity, we analyzed reactions of self-reactive DO11 cells to the systemic Ag in the absence of these subsets. This approach was used because Rag–/– mice could not be reconstituted with mature lymphocytes, particularly B cells, due to abnormalities in their lymphoid architecture. We initially postulated that the severe systemic reaction and Th1 development resulted from a deficiency of regulatory T cells. However, surprisingly, if sOVA Tg TCR{alpha}–/– mice, which only lack {alpha}{beta} T cells, are used as recipients for DO11 Rag–/– cells, i.e., if B cells are present, the clinical disease is less severe with less weight loss, and all animals survive (Fig. 1, A and B). This correlates with mild cellular infiltrates in the skin, which are much reduced compared with sOVA Tg Rag–/– recipients (Fig. 1, C and D). Thus, the absence of {alpha}{beta} T cells alone (which includes regulatory T cells) is not sufficient to allow for a severe pathologic reaction against the systemic Ag.

One likely explanation for the less severe disease in the sOVA Tg TCR{alpha}–/– mice is that there is less expansion than in the sOVA Tg Rag–/– mice, simply because there is less available space (9). To address this question, the transferred DO11 T cells were followed for cell numbers over time. As we had observed previously, DO11 cells that encounter the soluble Ag in WT Tg recipients undergo cycling with limited expansion (3- to 4-fold) followed by deletion and development of tolerance, as indicated by reduced IL-2 and complete lack of IFN-{gamma} production upon restimulation (Fig. 2) (14). In contrast, in the sOVA Tg Rag–/– recipients, the DO11 Rag–/– cells undergo massive expansion (Fig. 2A). Remarkably, when DO11 cells are transferred into sOVA Tg TCR{alpha}–/– recipients, the T cells undergo a similar expansion compared with sOVA Tg Rag–/– recipients (Fig. 2A). Thus, T cells in the host control the proliferation of Ag-recognizing lymphocytes and function to maintain homeostasis.



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  		FIGURE 2. Autoreactive T cells are less pathogenic in the presence of B cells. A total of 1 x 106 purified CD4+ DO11 Rag–/– cells were transferred into sOVA Tg WT, sOVA Tg Rag–/–, or sOVA Tg TCR{alpha}–/– mice or normal BALB/c recipients on day 0. A, Splenocytes were harvested at the indicated time points after transfer, and the total number of DO11 cells was determined by counting and flow cytometric analysis of KJ1-26+CD4+ cells. B, Splenocytes were harvested on day 5 after transfer, restimulated with OVA peptide and APC, and stained for intracellular cytokines. All plots are gated on KJ1-26+CD4+ cells. Numbers refer to percent of cytokine-positive cells. Representative plots are shown from one experiment of four with two to four mice per group. C, Splenocytes were harvested on day 5 or day 10 after transfer, restimulated with OVA peptide and APC, and stained for intracellular cytokines. Data are expressed as percentage of cytokine-positive gated KJ1-26+CD4+ cells pooled from two to four mice per group from one representative experiment of four.

 
Another possibility to explain the less severe reaction in the sOVA Tg TCR{alpha}–/– recipients, compared with the Rag–/– recipients, could be that effector differentiation is reduced. To address this question, the cytokine profiles of the DO11 cells were examined over time by intracellular staining. DO11 Rag–/– cells that have encountered their Ag for 5 or 10 days in sOVA Tg Rag–/– recipients produce abundant amounts of IL-2 and IFN-{gamma}, correlating with their severe clinical disease (Fig. 2, B and C). The effector differentiation is associated with up-regulation of the activation marker CD25 and down-regulation of CD62L (data not shown). Strikingly, DO11 cells transferred into the sOVA Tg TCR{alpha}–/– recipients produce less IL-2 and greatly reduced IFN-{gamma} compared with the sOVA Tg Rag–/– recipients (Fig. 2, B and C). This indicates that despite similar expansion of Ag-specific T cells, effector differentiation is reduced in the presence of B cells, presumably accounting for the less severe disease in the TCR{alpha}–/– sOVA Tg recipients.

B cells prevent effector differentiation and autoimmunity only in the absence of endogenous T cells

Because the sOVA Tg TCR{alpha}–/– recipients (lacking all {alpha}{beta} T cells) develop less disease than sOVA Tg Rag–/– recipients and no lethality, it is likely that B cells (which are normal in these mice) play a role in preventing the severe reaction of the DO11 T cells. The next set of experiments was designed to examine the relative contributions of endogenous T and B lymphocytes to the induction of tolerance. To address this question, we crossed sOVA Tg mice on a JHD–/– (B cell-deficient) background or on a TCR{alpha}–/– x JHD–/– double knockout (T and B cell-deficient) background and used these mice as recipients for adoptively transferred DO11 Rag–/– cells. Fig. 3A shows that sOVA Tg JHD–/– recipients show no clinical disease, similar to sOVA Tg WT mice. In contrast, sOVA Tg TCR{alpha}–/– x JHD–/– recipients develop severe systemic disease and show massive T cell infiltrates in the skin, recapitulating the histologic picture seen in sOVA Tg Rag–/– mice (Fig. 3, B and C).



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  		FIGURE 3. Absence of endogenous T cells is essential for pathogenicity of autoreactive T cells. A total of 1 x 106 CD4+-purified DO11 Rag–/– cells were transferred into sOVA Tg WT, sOVA Tg TCR{alpha}–/–, sOVA Tg JHD–/–, or sOVA Tg TCR{alpha}–/– x JHD–/– mice on day 0. A, Body weight is plotted as the change in percentage of the starting weight 10 days after T cell transfer. Data are pooled from two experiments (sOVA Tg WT, four mice; sOVA Tg TCR{alpha}–/–, six mice; sOVA Tg JHD–/–, four mice; sOVA Tg TCR{alpha}–/– x JHD–/–, six mice). B, Paraffin sections of skin of sOVA Tg TCR{alpha}–/– or sOVA Tg TCR{alpha}–/– x JHD–/– mice 10 days after T cell transfer were stained with H&E. C, Frozen sections of skin were stained with anti-CD4. One representative section from each group is shown.

 
Assays of cell numbers and functional responses showed that the transferred DO11 cells in the B cell-deficient recipients (sOVA Tg JHD–/–) behave like in the sOVA Tg WT recipients, showing only limited expansion followed by contraction (Fig. 4A). DO11 cells recovered on day 5 after transfer are functionally tolerant by IL-2 and IFN-{gamma} production (Fig. 4, B and C). However, if DO11 T cells are transferred into sOVA Tg TCR{alpha}–/– x JHD–/– recipients, the T cells undergo massive expansion (Fig. 4A) and develop effector function, just as in sOVA Tg Rag–/– recipients (Fig. 4, B and C).



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  		FIGURE 4. Endogenous T cells control expansion and Th1 effector differentiation of autoreactive T cells. A total of 1 x 106 CD4+-purified DO11 Rag–/– cells was transferred into sOVA Tg WT, sOVA Tg TCR{alpha}–/–, sOVA Tg JHD–/–, or sOVA Tg TCR{alpha}–/– x JHD–/– mice on day 0. A, Splenocytes were harvested at the indicated time points after transfer, and the total number of DO11 cells was determined by counting and flow cytometric analysis of KJ1-26+CD4+ cells. Data are from one representative experiment of two with two to four mice per group. B, Splenocytes were harvested 5 days after transfer, restimulated with OVA peptide and APC, and stained for intracellular cytokines. All plots are gated on KJ1-26+CD4+ cells. Representative plots are shown from one experiment of two with two to four mice per group. C, Splenocytes were harvested on day 5 or 10 after transfer, restimulated with OVA peptide and APC, and stained for intracellular cytokines. Data are expressed as percentage of cytokine-positive gated KJ1-26+CD4+ cells pooled from two to four mice per group from one representative experiment of four.

 
These results make two important points. First, the burst of expansion, which is limited by the presence of endogenous T cells, is critical for the breakdown of tolerance because tolerance induction is not affected in sOVA Tg JHD–/– mice. Second, the DO11 transfer into sOVA Tg TCR{alpha}–/– x JHD–/– recipients formally proves that B cells are the key players in the prevention of effector differentiation and not {gamma}{delta} T cells or other T cell populations that do not express the TCR{alpha} chain.

TCR down-modulation on self-Ag-specific T cells in the presence of B lymphocytes

Phenotypic analyses of DO11 cells that recognized the systemic Ag in the presence of endogenous B and/or T lymphocytes revealed that, in the presence of B lymphocytes (i.e., in TCR{alpha}–/– sOVA Tg recipients), the levels of the TCR and CD3, both surface and intracellular, are profoundly reduced, compared with Rag–/– and TCR{alpha}–/– x JHD–/– recipients (which lack both T and B cells) (Fig. 5 and data not shown). No TCR down-regulation is seen in either Rag–/– recipients or in TCR{alpha}–/– recipients that do not express sOVA (data not shown) demonstrating that TCR down-regulation in the presence of B cells depends on self-Ag recognition. TCR down-regulation has been associated with T cell Ag recognition and activation. However, the kinetics and the fact that no TCR down-regulation occurs in Rag–/– and TCR{alpha}–/– x JHD–/– recipients, despite strong effector differentiation, suggests that TCR down-regulation is mediated primarily by B cells and may serve as a mechanism of tolerance maintenance.



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  		FIGURE 5. TCR down-modulation in the presence of B cells. A total of 1 x 106 CD4+-purified DO11 Rag–/– cells was transferred into sOVA Tg TCR{alpha}–/–, sOVA Tg Rag–/–, sOVA Tg TCR{alpha}–/– x JHD–/–, or sOVA Tg JHD–/– on day 0. Splenocytes were harvested 10 days after transfer and stained for CD4 and KJ1-26 on the surface only or intracellularly after permeabilization. All plots are gated on KJ1-26+CD4+ cells. Representative histograms are shown from one experiment of two with two to four mice per group. The numbers indicate the mean fluorescence intensity of gated cells (shaded histograms). Mean fluorescence intensity of naive DO11 Rag–/– cells that had been transferred into BALB/c recipients was 1128 (surface) and 633 (intracellular), respectively (black histograms).

 
By studying the consequences of deficiency of a particular host lymphocyte population, we have tried to define the role of that population in the induction of T cell tolerance. These results demonstrate that normal, polyclonal T cells and B cells control different and perhaps sequential steps in the development of tolerance in naive T cells that encounter a systemic Ag. Endogenous T cells control the initial activation and proliferation of T cells that specifically recognize a self-Ag. The expansion that occurs in the absence of host T cells is critical for the breakdown of tolerance, because it does not occur in sOVA Tg WT or JHD–/– recipients, and in these recipients the transferred T cells become tolerant. Endogenous B cells, in contrast, do not prevent the accumulation of the potentially pathogenic T cells but limit the subsequent differentiation of these autoreactive lymphocytes into effector cells. Thus, B cells would be the second line in preventing autoimmunity once the initial control point at the stage of the T cell expansion has been passed.

The tolerogenic potential of Ag-presenting B cells has been suggested in previous studies (7, 20), but the underlying mechanisms remain obscure. For instance, B cells may provide a tolerogenic stimulus to T cells in a MHC-dependent fashion, as has been suggested for immature dendritic cells, or by an Ag-independent effect (21, 22). In our model, B cells may function to induce self-tolerance by several ways. First, because B cells are abundant and may be presenting self-Ag chronically, they may lead to down-modulation of the Ag receptor on self-reactive T cells or other proximal molecules in the TCR signaling pathway, e.g., through the E3-ubiquitin-ligase pathway (23, 24). The fact that both surface and intracellular TCR levels are down-regulated in sOVA Tg TCR{alpha}–/– recipients suggests that both internalization and degradation occur. B cells may also inhibit T cell differentiation by producing inhibitory cytokines such as IL-10 and TGF{beta} (25, 26).

Our data are the first evidence that different classes of endogenous lymphocytes may regulate different phases of a T cell response to a systemic self-Ag. It suggests that the relative contribution of T and B cells to immunity or tolerance is influenced by timing and the local environment at the site of Ag recognition. These results have important clinical implications in settings where one tries to induce tolerance in the presence of an empty host, e.g., in bone marrow transplantation or certain autoimmune diseases.


   Acknowledgments
 
We are indebted to C. Benitez for mouse typing We thank the members of the Abbas lab and Bluestone lab for helpful discussion.


   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 This work was supported by National Institutes of Health Grants RO1 AI64677 and PO1 AI35297 (to A.K.A.) and Deutsche Forschungsgemeinschaft Grants LO 808/1-1 and KN 533/1-1 (to J.L. and B.K.). Back

2 B.K. and J.L. contributed equally to this work. Back

3 Address correspondence and reprint requests to Dr. Abul K. Abbas, Department of Pathology, University of California at San Francisco, M-590, 505 Parnassus Avenue, San Francisco, CA 94143. E-mail address: aabbas{at}itsa.ucsf.edu Back

4 Abbreviations used in this paper: sOVA Tg, soluble OVA transgenic; WT, wild type. Back

5 B. Knoechel, J. Lohr, E. Kahn, and A. K. Abbas. Sequential development of IL-2-dependent effector and regulatory T cells in response to endogenous systemic antigen. Submitted for publication. Back

Received for publication March 21, 2005. Accepted for publication April 19, 2005.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 Disclosures
 References
 

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P. Reichardt, B. Dornbach, S. Rong, S. Beissert, F. Gueler, K. Loser, and M. Gunzer
Naive B cells generate regulatory T cells in the presence of a mature immunologic synapse
Blood, September 1, 2007; 110(5): 1519 - 1529.
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N. Forster, S. Gallinat, J. Jablonska, S. Weiss, H.-P. Elsasser, and W. Lutz
p300 Protein Acetyltransferase Activity Suppresses Systemic Lupus Erythematosus-Like Autoimmune Disease in Mice
J. Immunol., June 1, 2007; 178(11): 6941 - 6948.
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S. Deng, D. J. Moore, X. Huang, M.-M. Lian, M. Mohiuddin, E. Velededeoglu, M. K. Lee IV, S. Sonawane, J. Kim, J. Wang, et al.
Cutting Edge: Transplant Tolerance Induced by Anti-CD45RB Requires B Lymphocytes
J. Immunol., May 15, 2007; 178(10): 6028 - 6032.
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C. J. Callaghan, F. J. Rouhani, M. C. Negus, A. J. Curry, E. M. Bolton, J. A. Bradley, and G. J. Pettigrew
Abrogation of Antibody-Mediated Allograft Rejection by Regulatory CD4 T Cells with Indirect Allospecificity
J. Immunol., February 15, 2007; 178(4): 2221 - 2228.
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C. Bourgeois and B. Stockinger
CD25+CD4+ Regulatory T Cells and Memory T Cells Prevent Lymphopenia-Induced Proliferation of Naive T Cells in Transient States of Lymphopenia
J. Immunol., October 1, 2006; 177(7): 4558 - 4566.
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S. Inoue, W. W. Leitner, B. Golding, and D. Scott
Inhibitory effects of B cells on antitumor immunity.
Cancer Res., August 1, 2006; 66(15): 7741 - 7747.
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A. Mizoguchi and A. K. Bhan
A Case for Regulatory B Cells
J. Immunol., January 15, 2006; 176(2): 705 - 710.
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