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The Journal of Immunology, 2000, 164: 1658-1662.
Copyright © 2000 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: B Cells Promote CD8+ T Cell Activation in MRL-Faslpr Mice Independently of MHC Class I Antigen Presentation1

Owen T. M. Chan* and Mark J. Shlomchik2,*,{dagger}

* Section of Immunobiology and {dagger} Department of Laboratory Medicine, Yale University School of Medicine, New Haven, CT 06520


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Spontaneous CD8+ T cell activation in MRL-Faslpr mice is B cell dependent. It is unclear whether this B-dependent activation is mediated by direct Ag presentation via MHC class I proteins (i.e., cross-presentation) or whether activation occurs by an indirect mechanism, e.g., via effects on CD4+ cells. To determine how CD8+ T cell activation is promoted by B cells, we created mixed bone marrow chimeras where direct MHC class I Ag presentation by B cells was abrogated while other leukocyte compartments could express MHC class I. Surprisingly, despite the absence of B cell class I-restricted Ag presentation, CD8+ T cell activation was intact in the chimeric mice. Therefore, the spontaneous B cell-dependent CD8+ T cell activation that occurs in systemic autoimmunity is not due to direct presentation by B cells to CD8+ T cells.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Most CD4+ and CD8+ T cells in the autoimmunity-prone MRL-Faslpr strain (MRL/lpr) have an activated/memory phenotype (1, 2). This spontaneous activation and accumulation of T cells is highly B cell dependent (1, 3). This is not surprising for CD4+ T cells, given that B cells can specifically take up Ags and present them to CD4+ T cells (4). However, the mechanism for CD8+ T cell activation in lupus and why B cells should be critical for this activation is not clear (5). According to the classical pathway of class I Ag presentation of endogenously synthesized proteins, there is no obvious reason why B cells that specifically take up exogenous autoantigens should be essential APC for CD8+ T cells. However, B cells could be important if cross-presentation, a phenomenon by which exogenous Ags access the class I-restricted pathway, is operating, particularly if Ags endocytosed via surface Ig could be so presented (6).

Another possible mechanism by which B cells could promote CD8+ T cell activation is through the activation of CD4+ T cells. Activated Th cells can stimulate dendritic cells (DC)3 (e.g., via a CD40-mediated signal) to subsequently induce CTLs through cognate interactions (7). Since B cells are required to activate CD4+ T cells, the substantially greater numbers of activated and memory CD4+ T cells in B cell-intact mice could markedly enhance CD8+ T cell activation, thus explaining the effect of B cells.

To distinguish these models, we used ß2-microglobulin (ß2m)-deficient and B cell-deficient donors to create mixed bone marrow (BM) chimeras in which B cells lacked MHC class I proteins but in which class I was expressed in all other BM-derived cell compartments. In these chimeras, memory CD8+ T cell activation was intact, indicating that MHC class I-mediated Ag presentation by B cells to CD8+ T cells was not required for memory CD8+ T cell induction.


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

B cell-deficient JHD-MRL/lpr (JHD) mice were described (1). ß2m-deficient MRL/lpr breeding pairs were obtained from The Jackson Laboratory (Bar Harbor, ME). The JHD and ß2m strains were bred in our specific pathogen-free animal colony. MRL/lpr mice were obtained from The Jackson Laboratory. Animals were sex matched for each experiment.

FACS analysis and Ab reagents

These were as described (1, 8). The following additional reagents were used: anti-CD11b (M1/70-biotin; PharMingen, San Diego, CA), CD11c (HL3-biotin; PharMingen), and anti-H-2Kk (36-7-5-FITC; PharMingen).

BM chimera protocol

One day before BM infusion, recipient mice were injected i.p. with rabbit anti-asialo GM1 (Wako BioProducts, Richmond, VA) in sterile PBS to eliminate NK activity and to prevent rejection of ß2m-deficient BM (9). Dosages for each batch were adjusted according to the manufacturer’s instructions.

BM from the donor mice was extracted from the hind legs. RBCs were lysed using Tris-buffered ammonium chloride. We depleted Thy 1.2+ and B220+ cells from the BM via magnetic bead separation using biotinylated Abs, streptavidin beads, and a BS column (Miltenyi Biotec, Auburn, CA) on a VanbMACS separator (Miltenyi Biotec). BM infusions after cell depletion usually contained <5x 104 residual CD3+ cells per mouse.

The recipient mice were exposed to 700 rad from a 137Cs radiation source. A total of 5–10 x 106 cells was infused into the recipients. Chimeras were analyzed 13–23 wk later, an interval designed to allow time for spontaneous activation of reconstituted T cells to occur.

Statistics

Significance was assessed using the nonparametric Mann-Whitney U test. A p < 0.05 was considered to be significant. All analyses were conducted using StatView 4.5 (Abacus Concepts, Berkeley, CA) for the Macintosh.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mixed BM chimeras create immune systems in which only B cells lack MHC class I proteins

Mixed BM chimeras were created using BM from ß2m-deficient MRL/lpr (ß2m) mice and B cell-deficient JHD-MRL/lpr mice (JHD) (Table IGo). In such ß2m + JHD->JHD chimeras, T cells, macrophages, and DC are derived from both donor strains, with mixed populations deficient and sufficient in MHC class I expression. However, all of the mature B cells in this chimera should be MHC class I deficient. Therefore, in these chimeras, MHC class I Ag presentation is absent on only B cells whereas MHC class II Ag presentation is intact for all APCs. A series of control chimeras was also created (Table IGo).


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  		Table I. Predicted MHC class I expression of BM chimeric mice1

 
FACS analysis of cell subpopulations (T cells (Thy 1.2+), DC (CD11c+), macrophages and some DCs (CD11b+), B cells (CD19+)) from each type of chimera confirmed MHC class I expression and absence as predicted (Fig. 1GoA). The small number of CD19+ cells (class I+) detected in both the JHD->JHD and the ß2m + JHD ->JHD chimeras represent surface Ig- B lineage precursors that do emerge into the spleens of these B cell-deficient animals (see Ref. 10 , and note the CD19-gated histogram of the JHD mouse in Fig. 1Go). Mixed chimerism of MHC class I-negative and class I-positive populations from each cell subset can be detected in recipient mice receiving BM from ß2m-deficient and ß2m-intact donors. Note that in most cases, the class I-positive population predominates. Indeed, as demonstrated in Fig. 1GoB (left panel), even in recipients of ß2m-deficient marrow alone, a population of residual class I-positive cells is evident. We attribute these findings to resistance to engraftment of class I-negative hematopoietic stem cells (9) and autoreconstitution since a relatively low dose of irradiation was given. Notably, there was not a substantial enhancement of class I expression in mixed recipients compared with recipients of ß2m-deficient marrow alone (Fig. 1GoB ,right panel). However, it is only possible to state that surface class I expression was markedly reduced in the ß2m-deficient chimeras and not that it was entirely eliminated (11).



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  		FIGURE 1. FACS analysis confirms predicted MHC class I protein expression on subsets of BM-derived cells. Splenocytes from each chimera group were tested for the presence of H-2Kk. A, Histograms showing the level of H-2Kk on cells gated on various lineage markers as follows: T cells (Thy 1.2+), DC (CD11c+), macrophages and some DC (CD11b+), and B cells (CD19+). FACS analysis confirmed the expression of MHC class I predicted in Table IGo. Chimeras receiving BM from MHC class I-intact mice (JHD and WT) had H-2Kk-expressing populations. Chimeras receiving BM from MHC class I-deficient mice (ß2m) had H-2Kk-deficient populations. For the experimental group (ß2m + JHD->JHD), T cells, DC, and macrophages had mixed populations of class I-negative and class I-positive cells originating from both their donor BM sources. However, all of the B cells were class I negative. B, Histograms of splenocytes demonstrating the level of H-2Kk are shown. Left panel, Gated on Gr-1+ (myeloid) cells. The thick line represents the JHD->JHD chimera, in which all cells are expected to express class I; the thin line represents the ß2m->JHD chimera. Note that although there are class I-negative cells, there are also residual host-derived class I-positive cells indicating mixed chimerism. Right panel, Gated on CD19+ cells. The thick line represents the ß2m->JHD chimera; the thin line represents the ß2m + JHD->JHD chimera. Note that the histograms are superimposable.

 
CD8+ T cells are activated in the absence of B cell cognate interactions

At 13–23 wk after the BM transplant, splenocytes were analyzed by FACS to identify naive, activated, and memory subsets of CD4+ and CD8+ cells. These phenotypes have been classically established for CD4 cells as naive (CD44low,CD62Lhigh), activated (CD44high,CD62Lhigh), and memory (CD44high,CD62Llow) (12, 13, 14). These distinctions do not precisely apply to CD8 cells. Although CD44high remains a good marker of activated/memory CD8+ cells, the L-selectin low population includes both activated and memory CD8 cells (15, 16, 17, 18, 19). Therefore, for CD8+ cells, we will only distinguish naive (CD44low,CD62Lhigh) from activated and memory (CD44high), although we depict the CD62Lhigh and CD62Llow subsets of the CD44high cells. Representative CD44 and CD62L FACS staining on gated CD4+ and CD8+ cells from each chimera is shown in Fig. 2Go. Data from all of our experiments are summarized in Fig. 3Go.



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  		FIGURE 2. FACS analysis of splenic T cell activation phenotype in the BM chimeras. Splenocytes from each chimera group were stained with anti-CD44, anti-CD62L, and either anti-CD4 or anti-CD8. Dot plots of cells that were CD4+ (top row) or CD8+ (bottom row) are shown. Percentages of gated cells falling in each quadrant are indicated. Note that the T cell activation profile from the experimental group (ß2m + JHD->JHD) was similar to that of the positive control groups (ß2m->JHD, ß2m + WT->JHD, WT->JHD) and not the negative control group (JHD->JHD). Representative data from one experiment are shown; see Fig. 3Go for summary data.

 


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  		FIGURE 3. CD8+ T cell activation is intact despite the absence of MHC class I on B cells. The percentages of CD44low/CD62Lhigh, CD44high/CD62Lhigh, and CD44high,CD62Llow cells (as determined by FACS analysis in Fig. 3Go) for splenic CD4+ (A) and CD8+ (B) T cells were summarized from the chimeric animals analyzed in three separate experiments. Cell numbers for splenic CD4+ (C) and CD8+ (D) T cells are also shown. Despite the absence of MHC class I on the B cells of the experimental group (ß2m + JHD->JHD), CD8+ T cell activation and accumulation remained intact. CD4+ T cell activation and accumulation was also intact in these mice. Error bars represent 1 SD. Asterisks indicate p < 0.05 for comparisons to the JHD->JHD chimera. There was no significant difference between the ß2m + JHD->JHD (MHC class I-negative B cells) and ß2m + WT->JHD (MHC class I-positive B cells present) chimera groups (p = 0.17–0.93). Sample sizes for cell percentages were: JHD->JHD (9), ß2m->JHD (5), ß2m + WT->JHD (10), WT->JHD (10), and ß2m + JHD->JHD (8). Sample sizes for cell numbers were: JHD->JHD (6), ß2m->JHD (5), ß2m + WT->JHD (7), WT->JHD (6), and ß2m + JHD->JHD (6).

 
In the wild-type (WT) WT->JHD-positive control chimeras, the percentages of memory CD4+ and activated/memory CD8+ T cells were markedly greater than the percentage of naive cells (Fig. 3Go, A and B). Cell numbers of memory CD4+ T cells and activated/memory CD8+ T cells also were higher than those of naive cells (Fig. 3Go, C and D). These values were similar to those seen in intact MRL/lpr mice (1) and demonstrate that typical accumulation of activated/memory phenotype T cells also occurs in BM chimeras >13 wk posttransplantation. Conversely, in the JHD->JHD-negative control chimeras, the percentages of naive CD4+ and CD8+ T cells were higher than those in the WT->JHD-positive control chimeras whereas the percentages of memory CD4+ and activated/memory CD8+ T cells were lower. In absolute cell numbers, CD44high,CD62Llow T cell accumulation was much greater in the WT->JHD-positive control chimeras than in the JHD->JHD-negative control chimeras (Fig. 3Go, C and D). Again, B cell-deficient BM chimeras mirror the phenotype of unmanipulated JHD-MRL/lpr mice in having more naive and fewer activated/memory phenotype cells (1). These results reinforce the B cell dependence of activated/memory T cell accumulation for both CD4+ and CD8+ cells in the BM chimera setting.

The ß2m + JHD->JHD chimera (experimental group) had percentages and numbers of memory CD4+ T cells that were similar to those of the positive control, indicating that CD4+ T cell-B cell interactions were intact in the absence of MHC class I on B cells, as expected. Surprisingly, in these same mice, accumulation of activated/memory CD8+ T cells was also similar to the positive control, even though mature B cells in these mice lack ß2m and, therefore, surface class I expression. Thus, although B cells are required for activated/memory CD8+ T cell accumulation as shown in JHD->JHD chimeras and Ref. 1 , direct presentation of Ags by B cells via class I is not the mechanism. Comparable findings were observed in the B cell-intact control chimera (ß2m + WT->JHD), as expected. The ß2m->JHD chimera demonstrated reduced CD8+ activated/memory cell accumulation, although not quite to the same extent as the JHD chimera. One might have expected lack of activation since ideally no class I-positive APC should have been present. However, as shown in Fig. 1GoB (and data not shown), there was mixed chimerism due to residual host reconstitution and thus there were in fact some class I-positive APCs present.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Spontaneous accumulation of memory-phenotype CD8+ T cells in MRL/lpr mice is inhibited by almost 10-fold in the absence of B cells (1). In principle, B cells could be activating CD8+ T cells either directly (i.e., via cross-presentation) or indirectly (i.e., via CD4+ T cell activation and the subsequent effects of the CD4+ T cells). We designed a simple mixed BM chimera experiment to distinguish these possibilities. Results show that CD8+ T cell activation is intact in spite of marked reduction of class I expression by B cells that should have dramatically impaired cognate interactions with CD8+ T cells. This finding argues against a role for B cells in the cross-presentation of Ags to CTLs. It is similarly unlikely that presentation to CD8+ T cells via CD1 plays a role since CD1 expression is minimal or absent in the absence of ß2m. Likewise, it seems unlikely that class II-dependent presentation alone could explain the high levels of CD8+ T cell activation given the phenotype of ß2m knockout animals, which lack nearly all CD8+ T cells, showing that nearly all are class I restricted (11).

Since CD8+ T cell activation occurs in the absence of B cell contact, autoantibody (which is intact in the chimeras; data not shown) might play a role. However, Ab-mediated activation is not likely since CD8+ (and CD4+) T cell activation is intact in mIgM. MRL/lpr mice, which have B cells but are serum Ig deficient (3). Since neither cognate interactions nor autoantibody are required for the activation and accumulation of CD8+ T cells, B cells must act indirectly yet efficiently. We hypothesize that B cells promote CD8+ T cell activation first by activating CD4+ T cells. Then the activated/memory CD4+ T cells facilitate the activation of CD8+ T cells either through the production of cytokines (20, 21) and/or by "conditioning" an APC (probably a DC) through T cell help, which subsequently renders the APC capable of activating CTLs via cognate interactions (7). Additionally, we cannot rule out an effect of B cells secreting cytokines or chemokines (22, 23, 24, 25); although in a milieu of many activated T cells, we doubt that they would be limiting sources of such soluble factors.

The mechanisms of CD8+ T cell activation have direct relevance to disease pathogenesis in various autoimmune models. Depletion of CD8+ T cells in both the antiglomerular basement membrane and Heymann nephritis models inhibits disease (26, 27). Perhaps most relevant to the current findings, both glomerulonephritis and interstitial nephritis are ameliorated in ß2m-deficient MRL/lpr mice (28). Although decreased serum IgG1 levels may partly account for this (28), the results also suggest that CD8+ T cells play a role in lupus nephritis particularly in interstitial disease. Finally, CD8+ T cells are important effectors in graft-versus-host disease (29, 30) and nonobese diabetic mice (31, 32).

The current work provides mechanistic insight into the B cell dependence of CD8+ T cell activation by showing that B cells promote the activation of CD8+ T cells indirectly rather than through B cell contact. Given that B cells and CD8+ T cells are also both critical for disease in graft-versus-host-disease (29, 30, 33) and nonobese diabetic mice (31, 34, 35), the indirect mechanism by which B cells promote CD8+ T cell activation demonstrated in this report may reflect a general feature of alloimmune and autoimmune pathogenesis.


   Acknowledgments
 
We thank Eric Pamer, Warren Shlomchik, and Susan Wong for critically reading this manuscript and Brian Kinlan for his technical help. We thank Robert Eisenberg for useful discussions that led to the design of these experiments.


   Footnotes
 
1 This work was supported by National Institutes of Health Grant R01-AR44077. O.C. was supported by National Institutes of Health Training Grant AI07019. Back

2 Address correspondence and reprint requests to Dr. Mark J. Shlomchik, Department of Laboratory Medicine, 333 Cedar Street, Yale University School of Medicine, P.O. Box 208035, New Haven, CT 06520-8035. E-mail address: Back

3 Abbreviations used in this paper: DC, dendritic cell; BM, bone marrow; JHD, B cell-deficient JHD-MRL/lpr mice; ß2m, ß2-microglobulin; WT, wild type. Back

Received for publication August 2, 1999. Accepted for publication December 16, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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