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The Journal of Immunology, 2004, 173: 7135-7139.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Cbl-b: One of the Key Molecules Tuning CD28- and CTLA-4-Mediated T Cell Costimulation1

Dongdong Li*, István Gál*, Csaba Vermes*, Maria-Luisa Alegre, Anita S. F. Chong||, Lieping Chen#, Qing Shao**, Vyacheslava Adarichev*, Xuemei Xu*, Tamas Koreny*, Katalin Mikecz*,{dagger},§, Alison Finnegan{ddagger},§, Tibor T. Glant*,{dagger},{ddagger} and Jian Zhang2,*,§

Departments of * Orthopedic Surgery, {dagger} Biochemistry, {ddagger} Internal Medicine, and § Immunology/Microbiology, Rush University Medical Center, Chicago, IL 60612; Departments of Medicine and || Surgery, University of Chicago, Chicago, IL 60637; # Department of Immunology, Mayo Clinic, Rochester, MN 55905; and ** Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, Canada


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Cbl-b negatively regulates CD28-dependent T cell activation. In this report, we tested the hypothesis that CD28 and CTLA-4 have opposite roles in tuning T cell activation threshold by controlling the levels of Cbl-b protein expression. We demonstrate that CD28 costimulation potentiates TCR-induced Cbl-b degradation, whereas CTLA-4-B7 interaction is required for Cbl-b re-expression. In support of this finding, Cbl-b expression in CTLA-4 knockout (KO) T cells is significantly reduced, and treating CTLA-4KO mice with human CTLA-4Ig to block CD28-B7 interaction restores Cbl-b expression on T cells. Furthermore, CD28 and CTLA-4 costimulatory effects are compromised in Cbl-bKO T cells. These observations indicate that CD28 and CTLA-4 tightly regulate Cbl-b expression which is critical for establishing the threshold for T cell activation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
T cell activation is mediated by the TCR and coreceptors such as CD28 and CTLA-4 (1, 2, 3, 4). CD28 is constitutively expressed on the majority of CD4+ T cells, and is critical for optimal T cell activation (5). In contrast, CTLA-4, transiently expressed at the cell surface only after T cell activation, has been recognized as a negative regulator of T cell activation (4, 6, 7). In the absence of CD28 engagement, T cells require very high TCR occupancy and prolonged stimulation, whereas CD28 costimulation allows T cells to respond to lower degrees of TCR occupancy (8, 9, 10, 11, 12). In contrast, it has been suggested that CTLA-4 engagement raises the threshold for T cell responses (4, 6, 13). Thus, CD28 and CTLA-4 have opposite roles in the tuning of immune responses: CD28 decreasing and CTLA-4 increasing the threshold for T cell activation (4, 13).

Cbl-b plays an important role in regulating the threshold of signaling in T cells (14, 15). Loss of Cbl-b results in an increased susceptibility to the development of autoimmunity (14, 15). Furthermore, Cbl-b has been identified as a major susceptibility gene for the Komeda diabetes-prone rat (16). Therefore, Cbl-b is a key regulator of susceptibility to autoimmunity. It has been suggested that Cbl-b is involved in CD28-dependent T cell activation (14, 15, 17). Elimination of Cbl-b may favor CD28-mediated Vav activation possibly through a PI3K-dependent mechanism (18) because Cbl-b selectively regulates activity of Vav (14, 15) which is synergistically activated by CD28 costimulation (19, 20).

It appears that the levels of Cbl-b protein expression correlate with the rates of T cell activation. We were then interested in the idea that CD28 and CTLA-4 might control the threshold for T cell activation by regulating the levels of Cbl-b expression. To test this hypothesis, we used CD28 knockout (KO),3 Cbl-bKO, and CTLA-4KO mice. In combination with human CTLA-4Ig (hCTLA-4Ig), which blocks CD28- or CTLA-4-B7 interaction, we demonstrated that CD28 and CTLA-4 have opposite roles in controlling Cbl-b expression. Loss of Cbl-b uncouples the requirement of CD28 and CTLA-4 for T cell activation, indicating that Cbl-b is one of the key molecules that tune the threshold for T cell activation.


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

Female wild-type (WT) BALB/c and CD28KO BALB/c mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Cbl-bKO mice on the BALB/c background were obtained from Dr. J. M. Penninger (University of Toronto, Toronto, Ontario, Canada). CTLA-4 heterozygous mice on the C57BL/B6 background were maintained in our animal facility and intercrossed to generate CTLA-4KO mice which were used at age of 2 wk because these mice die at ages of 3–5 wk due to fatal lymphoproliferative disease (21, 22). All other mice were used for experiments at ages of 6–10 wk.

Reagents

The following reagents were purchased from BD Pharmingen (San Diego, CA): anti-CD3 (145-2C11), anti-CD28 (37.51), anti-CTLA-4 (9H10), and PE-conjugated anti-CTLA-4 (UC10-4F10-11). Anti-Cbl-b (G-1) and anti-src-homology domain 2-bearing protein tyrosine phosphatase-1 (SHP-1) (C-19) Abs were purchased from Santa Cruz Biotechnology (Santa Cruz, CA). T cell enrichment columns and recombinant human IgG1 Fc (rhIgG1 Fc) were obtained from R&D Systems (Minneapolis, MN). HRP-conjugated goat anti-rabbit IgG or rabbit anti-mouse IgG were purchased from Kirkegaard & Perry Laboratories (Gaithersburg, MD). hCTLA-4Ig was a gift from Dr. R. Peach (Bristol Myers Squibb, Princeton, NJ) (23).

T cell isolation and activation

Splenic T cells from mice were isolated (purity ≥90%) on T cell enrichment columns. For in vitro activation, T cells (5 x 106/ml) were stimulated for various time periods indicated by immobilized anti-CD3 (10 µg/ml) mAb and B7-1Ig (10 µg/ml) (24) in complete RPMI 1640. The cells were lysed in as previously described (17).

T cell proliferation assay

Naive or preactivated splenic T cells (2 x 106/ml) from different types of mice were cultured for 56 h or time indicated at 37°C in round-bottom 96-well plates immobilized with anti-CD3 (10 µg/ml) or anti-CD3 and B7-1Ig (10 µg/ml). The cells were pulsed with 1µCi of [3H]thymidine, and harvested 16 h later. The radioactivity was quantitated as previously described (17).

RT-PCR, immunoprecipitation, and Western blot

The conditions for RT-PCR, immunoprecipitation, and immunoblotting were described previously (17, 20, 25).

In vivo hCTLA-4Ig treatment

In vivo, CTLA-4KO mice were given injections of 50 µg/mouse hCTLA-4Ig or rhIgG1-Fc i.p. on the day of birth, and every other day thereafter until postnatal day 14 (26). Mice were sacrificed and analyzed immediately after the end of hCTLA-4Ig treatment.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
hCTLA-4Ig inhibits proliferation of WT T cells but enhances proliferation of CD28KO T cells

To test whether blockade of CD28- and CTLA-4-B7 interactions leads to a distinct outcome in proliferation of WT and CD28KO T cells, proliferation of WT and CD28KO T cells induced by immobilized anti-CD3 with or without B7-1Ig in the presence or absence of hCTLA-4Ig was performed. hCTLA-4Ig significantly abrogated TCR/CD28-induced WT T cell proliferation, whereas it greatly enhanced CD28KO T cell proliferation (Fig. 1). The enhanced proliferation of CD28KO T cells by hCTLA-4Ig treatment suggests that a blockade of CTLA-4-B7 interaction is involved in the regulation of T cell proliferation in these cells.



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  		FIGURE 1. hCTLA-4Ig inhibits proliferation of WT T cells but enhances proliferation of CD28KO T cells. T cells from naive WT and CD28KO mice were stimulated for 72 h with immobilized anti-CD3 (10 µg/ml) or immobilized anti-CD3 and B7-1Ig (10 µg/ml) in the presence or absence of hCTLA-4Ig (25 µg/ml), and T cell proliferation was determined by [3H]thymidine incorporation. As a control, hCTLA-4Ig was added to T cells in the absence of anti-CD3 and B7-1Ig. Data represent the mean ± SD.

 
CTLA-4-B7 interaction potentiates TCR-induced Cbl-b re-expression

Recently, we have demonstrated that CD28 stimulation can promote TCR-induced Cbl-b ubiquitination itself, indicating that Cbl-b is a key molecule involved in the regulation of both TCR- and CD28-signaling pathways (17). Because CTLA-4 has an opposing role to CD28 in the regulation of T cell activation, we hypothesized that CTLA-4 costimulation might up-regulate Cbl-b expression. Cbl-b was weakly re-expressed at 48–72 h following TCR stimulation, whereas TCR/B7-1 costimulation induced strong re-expression of Cbl-b, occurring at 36 h, becoming evident at 48–72 h after stimulation (Fig. 2A, upper panel). Interestingly, the kinetics of Cbl-b expression by WT T cells coincide with the kinetics of CTLA-4 expression (Fig. 2B). These results suggest that the re-expression of Cbl-b in WT T cells at 36–72 h following TCR/B7-1 stimulation may be potentiated by CTLA-4-B7 interaction.



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  		FIGURE 2. CTLA-4-B7 interaction potentiates TCR-induced re-expression of Cbl-b. A, Upper panel, WT T cells were stimulated for 8, 24, 36, 48, and 72 h with immobilized anti-CD3 (10 µg/ml) or anti-CD3 and B7-1Ig (10 µg/ml), and lysed. The cell lysates were immunoprecipitated with anti-Cbl-b, and blotted with anti-Cbl-b. The same supernatants were immunoprecipitated with anti-SHP-1 and blotted with anti-SHP-1. A, Lower panel, WT T cells were stimulated for 24, 48, and 72 h with immobilized B7-1Ig, and lysed. Cbl-b expression was determined. B, WT and CD28KO T cells were stimulated for 12, 24, 36, 48, and 72 h with immobilized anti-CD3 or anti-CD3 and B7-1Ig, and stained with PE-conjugated anti-CTLA-4. The expression of CTLA-4 was determined by flow cytometry. C, CD28KO T cells were stimulated for 8, 12, 24, 36, 48, and 72 h with immobilized anti-CD3 and B7-1Ig in the presence or absence of hCTLA-4Ig (25 µg/ml), and lysed. The cell lysates were immunoprecipitated with anti-Cbl-b, and blotted with anti-Cbl-b. D, WT T cells were stimulated for 72 h with immobilized anti-CD3, anti-CD3 plus anti-CD28, or anti-CD3 plus anti-CTLA-4. The cells were lysed and immunoprecipitated with anti-Cbl-b, and blotted with anti-Cbl-b. The same supernatants were immunoprecipitated and blotted with anti-SHP-1. In parallel, T cell proliferation under the same condition was determined. E, WT T cells were activated for 72 h with immobilized anti-CD3 and B7-1Ig, and activated T cells were then stimulated for 24 and 48 h with immobilized anti-CD3 or anti-CD3 plus anti-CTLA-4. Alternatively, CD28KO T cells were activated for 72 h with immobilized anti-CD3, and activated CD28KO T cells were stimulated for 24, 48, and 72 h with immobilized anti-CD3 or anti-CD3 and B7-1Ig. Cbl-b expression was determined. F, CD28KO T cells were stimulated as E, and activated CD28KO T cells were restimulated for 48 and 72 h with immobilized anti-CD3 or anti-CD3 and B7-1Ig. Proliferation of activated CD28KO T cells was determined.

 
To determine the effect of CTLA-4 on Cbl-b expression, CD28KO T cells were stimulated with immobilized anti-CD3 or anti-CD3 and B7-1Ig for 0, 8, 12, 24, 36, 48, and 72 h in the presence or absence of hCTLA-4Ig. Cbl-b degradation kinetics were much slower in both TCR- and TCR/B7-1-stimulated CD28KO T cells than in WT T cells. Stimulation of CD28KO T cells with immobilized anti-CD3 induced weak Cbl-b re-expression which occurred only at 72 h of stimulation. In comparison, Cbl-b re-expression was clearly seen at 48–72 h in CD28KO T cells following TCR/B7-1 costimulation, and this Cbl-b re-expression was inhibited by addition of hCTLA-4Ig which blocks CTLA-4-B7-1 interaction (Fig. 2C). Indeed, coligation of CD3 and CTLA-4 resulted in an increase in Cbl-b expression, which correlated with suppression of T cell proliferation (Fig. 2D, lower panel). Taken together, our data clearly indicate that CTLA-4-B7 interaction is involved in the up-regulation of Cbl-b expression after initial degradation. Because both CTLA-4 and Cbl-b negatively regulate lipid raft aggregation (27, 28), and Cbl-bKO and CTLA-4KO T cells are resistant to induction of T cell anergy (29, 30), it suggests that Cbl-b may be a major mediator of this CTLA-4 signaling pathway.

Effective signaling of naive T cells occurs within a few hours of contact between a T cell and an APC (31, 32). Therefore, Cbl-b re-expression may be involved in the second round of T cell-APC interaction. To further verify the role of CTLA-4 in Cbl-b re-expression, WT T cells were activated for 72 h with immobilized anti-CD3 and B7-1Ig to induce CTLA-4 expression. Activated WT T cells were then restimulated for 24 and 48 h with immobilized anti-CD3 or anti-CD3 plus anti-CTLA-4. TCR stimulation induced transient re-expression of Cbl-b, which was greatly increased by CTLA-4 costimulation (Fig. 2E). Similar results were obtained from preactivated CD28KO T cells when they were stimulated with anti-CD3 or anti-CD3 plus B7-1. In contrast, B7-1 stimulation alone did not transmit a signal to induce Cbl-b expression in activated CD28KO T cells (Fig. 2E). In keeping with the induction of Cbl-b after TCR/CTLA-4 engagement, ligation of CTLA-4 by B7-1 significantly inhibited TCR-induced proliferation of preactivated CD28KO T cells (Fig. 2F). These data indicate that CTLA-4-B7 interactions potentiate TCR-induced Cbl-b re-expression, supporting the notion that CD28 and CTLA-4 quantitatively modify TCR signaling (4, 13, 33).

CD28 and CTLA-4 regulate Cbl-b expression via distinct mechanisms

To determine whether Cbl-b expression mediated by B7-1 stimulation is regulated at transcriptional or posttranslational levels, WT and CD28KO T cells were stimulated with immobilized anti-CD3 and B7-1Ig for 0, 24, 48, and 72 h, and RNA was isolated. Cbl-b mRNA expression detected by RT-PCR in both WT and CD28KO T cells was significantly up-regulated after stimulation, being evident in WT T cells (Fig. 3). These results together with previous results shown in Fig. 2 clearly indicate that Cbl-b is regulated at both transcriptional and posttranslational levels by CD28 costimulation.



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  		FIGURE 3. Cbl-b expression is controlled at both the transcriptional and posttranslational levels. WT and CD28 KO T cells were stimulated for 0, 24, 48, and 72 h with immobilized anti-CD3 and B7-1Ig, and expression of Cbl-b mRNA was determined.

 
A balance between CD28 and CTLA-4 signaling may determine the degree of T cell activation (1, 4). Loss of CTLA-4 leads to an imbalance of CD28 and CTLA-4 which presumably lowers the threshold for T cell activation, resulting in fatal lymphoproliferative disease (21, 22). To confirm the role of CD28 and CTLA-4 in the regulation of Cbl-b expression, CTLA-4KO T cells were used. Cbl-b expression in CTLA-4KO T cells was significantly reduced and rapidly diminished after anti-CD3 stimulation compared with that in CTLA-4 WT T cells (Fig. 4A). To further confirm this, CTLA-4KO mice were treated with hCTLA-4Ig or rhIgG1-Fc every other day after birth for 2 wk. It has been shown that treating CTLA-4KO mice with CTLA-4Ig can rescue these mice from fatal lymphoproliferative disease (26). In vivo, hCTLA-4Ig treatment significantly enhanced Cbl-b expression compared with that in rhIgG1-Fc-treated CTLA-4KO T cells (Fig. 4B). To determine whether CTLA-4 regulates Cbl-b at the transcriptional and/or posttranslational levels, CTLA-4 WT and KO T cells were stimulated for 0, 24, 48, and 72 h with immobilized anti-CD3 plus B7-1Ig, and Cbl-b mRNA was detected. Surprisingly, although Cbl-b mRNA expression was higher in CTLA-4KO T cells than WT T cells, it disappeared after stimulation, and was not detectable during the entire stimulation period. Consistent with this finding, no Cbl-b protein was detected in CTLA-4KO T cells after stimulation (Fig. 4C). Therefore, CTLA-4 may primarily regulate Cbl-b at the transcriptional levels, suggesting that CTLA-4 and CD28 regulate Cbl-b expression via distinct mechanisms. Taken together, our data strongly support the notion that hyperactivation of T cells by loss of CTLA-4 may in part be ascribed to the elimination of Cbl-b.



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  		FIGURE 4. Cbl-b expression is diminished in CTLA-4KO T cells. A, T cells from CTLA-4 WT and CTLA-4KO mice were stimulated for 30 min with anti-CD3 or left unstimulated, and lysed. Cbl-b expression was determined. The same supernatants were immunoprecipitated with anti-SHP-1, and blotted with anti-SHP-1. B, CTLA-4KO mice were treated with hCTLA-4Ig or rhIgG1-Fc (50 µg/mouse) from birth every other day for 2 wk. At the end of the treatment, mice were sacrificed. T cells from CTLA-4KO mice receiving hCTLA-4Ig or rhIgG1-Fc treatment were isolated, and Cbl-b and SHP-1 expression was determined. C, CTLA-4 WT and CTLA-4KO T cells were stimulated for 0, 24, 48, and 72 h with immobilized anti-CD3 and B7-1Ig, and the expression of Cbl-b mRNA and protein was determined. The fold induction of Cbl-b mRNA expression relative to GAPDH over time is indicated.

 
CD28 and CTLA-4 costimulatory effects are compromised in Cbl-bKO mice

It has been shown that loss of Cbl-b uncouples the requirement for CD28 costimulation (14, 15). Therefore, one would also expect that loss of Cbl-b should uncouple the requirement of CTLA-4 for T cell activation. As expected, Cbl-bKO T cells did hyperproliferate in response to anti-CD3 stimulation, and costimulation with anti-CD28 or anti-CTLA-4 did not enhance or inhibit CD3-induced T cell proliferation (Fig. 5). Cbl-bKO T cells are not susceptible to the inhibitory effect of CTLA-4 engagement, suggesting that expression of Cbl-b is necessary for the function of CTLA-4.



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  		FIGURE 5. Loss of Cbl-b uncouples the requirement for CD28 or CTLA-4 in T cell activation. WT and Cbl-bKO T cells were stimulated for 72 h at 37°C with immobilized anti-CD3, anti-CD3 plus anti-CD28, or anti-CD3 plus anti-CTLA-4. T cell proliferation was determined.

 
In summary, our data reveal that CD28 costimulation promotes TCR-induced Cbl-b degradation, whereas CTLA-4-B7 interaction potentiates TCR-induced Cbl-b re-expression. These results indicate that CD28 and CTLA-4 control T cell activation and proliferation at least in part by regulating Cbl-b expression.


   Acknowledgments
 
We thank Drs. R. Peach and J. M. Penninger for providing hCTLA-4Ig construct and Cbl-bKO mice, respectively, and we thank S. Velins for assistance in preparation of the manuscript.


   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 grants from the National Institutes of Health (AR047412, AR049047, and AR049775; to J.Z.), and a grant-in-aid (0355509Z) from the American Heart Association (to J.Z.). Back

2 Address correspondence and reprint requests to Dr. Jian Zhang at the current address: Section of Nephrology, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC 5100, Suite S-521, Chicago, IL 60637. E-mail address: jzhang{at}medicine.bsd.uchicago.edu Back

3 Abbreviations used in this paper: KO, knockout; WT, wild type; hCTLA-4Ig, human CTLA-4 Ig; rhIgG1 Fc, recombinant human IgG1 Fc; SHP-1, src-homology domain 2-bearing protein tyrosine phosphatase-1. Back

Received for publication April 15, 2004. Accepted for publication October 18, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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