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The Journal of Immunology, 2004, 173: 2928-2932.
Copyright © 2004 by The American Association of Immunologists

CUTTING EDGE

Cutting Edge: Critical Role for CD5 in Experimental Autoimmune Encephalomyelitis: Inhibition of Engagement Reverses Disease in Mice1

Robert C. Axtell*, Matthew S. Webb{dagger}, Scott R. Barnum{dagger} and Chander Raman2,{dagger}

Departments of * Medicine and {dagger} Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
The induction phase of experimental autoimmune encephalomyelitis (EAE) in mice is T cell dependent and coreceptors that regulate T cell activation modulate disease development. We report here that mice lacking CD5, an important modulator of T cell activation, exhibit significantly delayed onset and decreased severity of EAE. The resistance to EAE in CD5–/– mice was not due to the inability of T cells to respond efficiently to stimulation with MOG35–55 but was associated with the presence of elevated frequency of apoptotic activated T cells in spleens and DLN. We also observed a net decrease in peripheral activated CD4+ T cells in CD5–/– spleens and DLN 10 days after immunization. We further show that in vivo blockade of CD5 engagement after induction of EAE by soluble CD5-Fc, a treatment that induces elimination of activated T cells, promoted recovery from EAE. Our studies indicate that CD5 regulates survival of activated T cells and provides a target for treatment of T cell-dependent autoimmune diseases such as multiple sclerosis.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Regulating activation of T cells by coreceptors is a critical event in the induction and progression of experimental autoimmune encephalomyelitis (EAE).3 Animals with genetic disruptions of CD28 costimulation or signaling do not develop EAE (1, 2). Other studies report successful treatment of EAE by using mAbs or soluble CTLA-4 to block CD28 from binding to its ligands, B7-1 and B7-2 (3, 4, 5). PD-1, a B7 family member, is a receptor that regulates T cell activation and has been implicated in altering progression of EAE. However, unlike CD28, PD-1 is a negative regulator of T cell activation and therefore experiments that block PD-1 signaling using antagonistic Abs increased disease severity in mice (6).

CD5, a receptor expressed on all developing and mature thymocytes, is an important regulator of T cell activation (7). The known function of CD5 is to regulate signaling negatively through the Ag receptor in thymocytes and mature T cells. CD5–/– thymocytes and mature T cells are hyperresponsive to Ag stimulation, demonstrating that this receptor attenuates signals through the TCR and regulates the threshold of signaling (7, 8, 9, 10). The level of expression of CD5 on thymocytes and peripheral T cells is proportional to the affinity/avidity of the TCR:peptide:MHC and may be associated with its negative regulatory function (11, 12, 13).

In this study, we examined the contribution of CD5 in development and progression of EAE. We used MOG35–55 peptide to induce EAE in wild-type (WT) and CD5–/– C57BL/6 mice and then we examined the clinical course of the disease. Remarkably, we found that CD5–/– mice had both a delayed onset and decreased disease severity. This resistance of CD5–/– mice to EAE was associated with elevated activation-induced cell death (AICD). We also found that acute expression of a soluble CD5-Fc fusion protein 2 wk after induction of EAE with MOG35–55 reversed the progression of disease in mice. Overall, these results indicate that CD5 is involved in regulating T cell survival and blocking this activity is therapeutically beneficial for treatment of EAE in mice.


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

C57BL/6 mice were purchased from The Jackson Laboratory (Bar Harbor, ME). CD5–/– mice were backcrossed into C57BL/6 for 10 generations. All animals were housed and treated in accordance to National Institutes of Health guidelines.

EAE induction

Mice were immunized with 150 µg of MOG35–55 peptide (Biosynth International, Lewisville, TX) that was modified from a previously described protocol, and EAE symptoms were monitored daily for 30–35 days using a standard clinical score ranging from 0 to 6 (14). Briefly, mice received a single immunization of peptide in CFA on day 0, followed by pertussis toxin on days 0 and 2. Animals with a clinical score <2 as defined by loss of tail tone are considered free of clinical disease.

T cell proliferation

Single-cell suspensions from spleens or draining lymph nodes (DLN) obtained 4 and 10 days after EAE induction were cultured in 96-well plates at 5 x 105 cells/well with different concentrations of MOG35–55 peptide or 10 µg/ml anti-CD3, clone 145-2C11(NCCC, Minneapolis, MN) in triplicate. After 48 h, cultures were pulsed with [3H]thymidine for an additional 18 h, and incorporation of thymidine was determined.

Flow cytometry and apoptosis assay

Single-cell suspensions of spleen and DLN cells were incubated with anti-CD16/32 (2.4G2, FcR block) and then stained with anti-CD4-FITC (L3T4), anti-pan V{beta}8-FITC (F23.1), anti-CD4-PE (L3T4), anti-CD8-PE (53-6.7), anti-CD69 PE, or anti-CD4-biotin (L3T4) (eBiosciences, San Diego, CA) and 7-aminoactinomycin D (7-AAD; BD Pharmingen, San Diego, CA). Anti-CD8-Alexa 647 (53-6.7) was donated by Dr. J. George (University of Alabama at Birmingham, Birmingham, AL). To assay for early apoptotic events in T cells, we measured loss of mitochondrial membrane potential by incubating cells with dihexyloxacarbocyanine (DiOC6; Molecular Probes, Eugene, OR) at a final concentration of 20 nM for 15 min at 37°C before staining (15). Stained cells were analyzed using a FACSCalibur (BD Biosciences, San Jose, CA). For in vitro apoptosis assay, splenocytes were cultured for 24 h in 96-well plates at 1 x 106 cells/well with different concentrations of anti-CD3. Frequency of apoptotic T cells was identified by staining with annexin V and 7-AAD (BD Pharmingen) after gating out B220+ (anti-B220-biotin, RA3-6B2) cells. Streptavidin-allophycocyanin (BD Pharmingen) was used to detect biotinylated Abs.

Recombinant adenovirus generation and treatment of mice

Recombinant adenovirus encoding murine (Ad-mCD5Fc) or human soluble CD5 (Ad-hCD5Fc) was generated by cloning the extracellular region of human or murine CD5 in-frame with the Fc and hinge region of human IgG1 in pShuttleCMV (gift from Dr. T. Zhou, University of Alabama at Birmingham) as described previously (16). CD5-sufficient mice were treated with a single injection of 108 viral particles, i.p., of either Ad-mCD5Fc or Ad-hCD5Fc 14 days after induction of EAE. Fusion proteins were detected in serum by an anti-human IgG1 (Jackson ImmunoResearch Laboratories, West Grove, PA) ELISA 3 days after treatment.

Staphylococcal enterotoxin B (SEB) injections and viral treatment

WT mice were treated with a single injection of 108 viral particles, i.p., of either Ad-mCD5Fc or Ad-GFP 1 day before an injection of SEB (85 µg; Sigma-Aldrich, St. Louis, MO). Splenocytes were harvested 2 days after SEB injection and stained as described above.

Statistics

Results were analyzed for statistical significance using a two-tailed Student’s t test.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
To assess the role of CD5 in EAE, we followed disease progression in CD5–/– and CD5+/+ C57BL/6 mice immunized with MOG35–55. Since it is established that the lack of CD5 lowers the threshold for activation through the Ag receptor, we predicted that EAE symptoms would be exacerbated in CD5–/– mice (7, 8, 9, 10). However, contrary to our expectations, EAE in CD5–/– mice was significantly delayed in onset and attenuated in severity (Fig. 1 and Table I). The incidence of disease, however, was similar in both CD5+/+ and CD5–/– mice.



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  		FIGURE 1. Clinical course of MOG35–55-induced EAE in CD5+/+ and CD5–/– mice. EAE was induced in CD5+/+ and CD5–/– mice following s.c. immunization with 150 µg MOG35–55 as described in Materials and Methods. Results are the mean clinical score (bars represent SEM) from two independent experiments.

 

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  		Table I. EAE disease severity, onset, and incidence in CD5–/– and WT mice

 
Since CD5 modulates thymic selection and/or alters repertoire, the protection that CD5 deficiency provides in EAE may reflect a lower frequency of myelin oligodendrocyte glycoprotein (MOG)-specific T cells in the periphery. To address this possibility, we stimulated spleen and DLN cells obtained 4 days after induction of disease with MOG35–55 peptide and found that at concentrations of 1 and 5 µg/ml, T cells from CD5–/– mice proliferated more efficiently than those from CD5+/+ mice (Figs. 2, A and B). Furthermore, at 4 days after immunization, the frequency of activated CD4+ T cells (CD69+) in spleens and DLN was greater in CD5–/– mice than in CD5+/+ mice (Fig. 2C). These results demonstrate that T cells from CD5–/– mice respond to MOG35–55 efficiently and therefore rules out the possibility that the resistance to EAE in CD5–/– mice is due to lack of MOG-specific T cells.



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  		FIGURE 2. Resistance of CD5–/– mice to EAE is due to enhanced AICD. In vitro MOG35–55 peptide induced proliferation of spleen (A) and DLN (B). from CD5+/+ and CD5–/– mice obtained 4 and 10 days after MOG35–55 treatment. Results are the mean cpm ± SD of triplicates and represents one of three independent experiments. C, Frequency of CD4+ cells expressing CD69 in spleens and DLN from CD5+/+ and CD5–/– mice 0, 4, and 10 days after immunization with MOG35–55 peptide. Data represent the mean ± SD of seven mice from each group. D, Frequency of apoptotic (DiOC6low) CD4+ cells from spleens of CD5+/+ and CD5–/– mice 0, 4, and 10 days after EAE induction. Data represent mean ± SD from three independent experiments, three mice per group. *, p < 0.1; **, p < 0.05; ***, p < 0.01.

 
In contrast to day 4, CD5–/– T cells harvested 10 days after induction of EAE proliferated poorly to restimulation with MOG compared with WT; however, proliferation to anti-CD3 was not affected (Figs. 2, A and B and data not shown). Furthermore, we also observed that on day 10 the frequency of activated CD4+ T cells in DLN and spleens of CD5–/– mice had significantly decreased from day 4 (Fig. 2C). In contrast, the frequency of activated CD4+ T cells in spleens and DLN from CD5+/+ mice continued to increase. On day 10, the CD4 T cells in spleens and DLN of CD5–/– mice was lower compared with those of CD5+/+ mice (spleen: 17.5 ± 1.1 vs 20.6 ± 1.3; DLN: 17.0 ± 0.6 vs 26.1 ± 1.1, respectively; n = 7). These results suggest that the immune response was in the contraction phase in CD5–/– mice, whereas in CD5+/+ mice, it was still in the expansion phase. Consistent with this prediction, we observed that frequency of apoptotic (DiOC6low/7-AAD–) CD4+ T cells was significantly greater in CD5–/– mice than in CD5+/+ mice on day 10 in the spleen and on both days 4 and 10 in the DLN (Fig. 2D). To directly test whether the lack of CD5 is associated with accelerated AICD, we cultured CD5+/+ and CD5–/– splenic T cells using various concentrations of anti-CD3 for 24 h, followed by staining with annexin V and 7-AAD. The results show that there is a higher frequency of cells undergoing apoptosis (annexin V+/7-AAD–) among anti-CD3-stimulated CD5–/– T cells compared with CD5+/+ T cells (Fig. 3). Based on these data, we propose that the delayed onset and decreased severity of EAE in CD5–/– mice reflects the rapid activation and proliferation followed by enhanced death of MOG-specific CD4+ T cells. Overall, these experiments indicate that CD5 may be involved in regulating T cell survival in addition to its established role as an attenuator of proximal TCR/CD3 signaling. Our previous findings that show a higher incidence of AICD following in vivo activation of CD5–/– T cells and a recent report indicating that survival of autoreactive T cells correlates with TCR and CD5 density is consistent with our current observations (12, 13, 17).



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  		FIGURE 3. In vitro apoptosis in CD5+/+ and CD5–/– splenocytes after culturing with different concentrations of anti-CD3 (0–1 µg/ml) for 24 h. A, Dot plots show annexin V and 7-AAD frequencies from the B220-subtracted population. B, Percent viable T cells (annexinV–/7-AAD–) were normalized to unstimulated cells. Results are the mean ± SD from five independent experiments.

 
CD5 may regulate survival through activation of the serine-threonine kinase CK2, a critical regulator of cell survival and apoptosis (18). We previously showed that engagement of CD5 activates CK2 (19), an activity that would be lacking in CD5–/– T cells. This led us to predict that blockade of CD5 engagement will enhance AICD of activated T cells by inhibiting CK2-dependent survival signals and be a beneficial treatment of EAE. To investigate this hypothesis, we treated CD5+/+ mice 14 days after induction of disease with an adenovirus, Ad-mCD5Fc, that encodes the extracellular region of murine CD5 fused to the Fc portion of human IgG1. The use of this recombinant virus in mice allows for the expression of elevated and sustained levels of CD5-Fc fusion protein similar to that of Ad-CTLA4-Ig treatment studies (20). Our rationale behind this approach was to use soluble mCD5Fc in mice to block the endogenous ligand of CD5 from binding to the receptor. As a control, we treated a group of mice with Ad-hCD5Fc. Within 3 days of treatment, serum of mice treated with Ad-mCD5Fc or Ad-hCD5Fc contained 1.7 ± 0.7 and 4.8 µg/ml ± 0.7 recombinant CD5-Fc protein, respectively. An analysis of disease progression of all animals showed that treatment of mice with Ad-mCD5Fc arrested disease, whereas Ad-hCD5Fc treatment did not (Fig. 4A and Table II). Remarkably, only one of five mice that had a clinical score <2 at the time of treatment with Ad-mCD5Fc developed disease; in contrast, all mice treated with Ad-hCD5Fc developed disease (Fig. 4B and Table II). Even among the mice that had disease (≥2) at the time of Ad-mCD5Fc treatment, five of seven mice exhibited a decrease in their clinical score of at least 1 (Fig. 4C and Table II). This recovery was significantly greater than that of Ad-hCD5-Fc-treated mice where only one of five recovered within 4 days. We predicted that recovery following the expression of mCD5-Fc in mice was due to the elimination of activated T cells as a result of CD5 blockade. To test this prediction, we analyzed the effect Ad-mCD5Fc treatment on V{beta}8+ T cells following activation with SEB in vivo. We found that spleens of Ad-mCD5-Fc-treated mice had nearly a 30% loss in frequency of V{beta}8+CD4+ cells compared with Ad-hCD5Fc-treated controls (Fig. 4D). This diminished population of V{beta}8+CD4+ cells was due to an increase of AICD, since we observed a significant increase in apoptotic (DiOC6low) V{beta}8+CD4+ cells in Ad-mCD5Fc-treated mice compared with those of Ad-hCD5Fc controls (Fig. 4E). These data demonstrate that soluble CD5 enhances death of activated T cells by AICD.



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  		FIGURE 4. A–C, Treatment with Ad-mCD5Fc blocks progression of EAE. EAE was induced in CD5+/+ mice as described in Materials and Methods. Fourteen days after EAE induction, mice were injected with 108 adenoviral PFU of Ad-mCD5Fc or Ad-hCD5Fc, i.p., or left untreated. Clinical scores were monitored for 30 days: Data were analyzed in A, all mice used in this study (Ad-mCD5Fc, n = 12; Ad-hCD5Fc, n = 11; No treatment, n = 10); B, mice treated with clinical scores <2 (Ad-mCD5Fc, n = 5; Ad-hCD5Fc, n = 6; No treatment, n = 6); C, mice treated with clinical scores ≥2 (Ad-mCD5Fc, n = 7; Ad-hCD5Fc, n = 5; No treatment, n = 4); and D–E, Ad-mCD5Fc treatment enhances AICD in V{beta}8 cells in mice injected with SEB. D, Frequency of V{beta}8+ T cells in spleens from mice treated with Ad-mCD5Fc or Ad-hCD5Fc after immunization with SEB. Results are the mean ± SD of five mice from each group. E, Percentage of apoptotic (DiOC6low) V{beta}8 CD4+ cells in spleens from mice treated with Ad-mCD5Fc or Ad-hCD5Fc after immunization with SEB. Results are the mean ± SD of five mice from each group. *, p < 0.05; **, p < 0.01.

 

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  		Table II. EAE disease severity, incidence, and recovery after adenovirus treatment

 
The assumption here is that CD5-Fc functions as a decoy receptor that blocks the engagement of endogenous CD5 by its ligand, thereby counteracting prosurvival signals. Alternative explanations are that CD5-Fc exerts its activity by preventing recruitment of CD5 to the immune synapse or binding to another cell surface protein. We believe the latter is unlikely, as we observe no binding of CD5-Fc to any cell surface protein (data not shown). The protection from EAE provided by CD5-Fc is greater than the resistance of CD5–/– mice to disease (Fig. 1 and Fig. 4, A–C). This result may reflect that T cells in CD5–/– mice lack both the inhibitory activity of CD5, which is considered engagement independent and survival activity, which is engagement dependent (10, 19). Alternatively, the difference may simply represent that CD5–/– mice, chronically lacking CD5, have developed compensatory changes, which is unlikely to occur when CD5 function is acutely lost such as following CD5-Fc treatment. The precise signaling events that regulate survival through CD5 are currently under investigation. However, we predict that CD5 engagement in activated T cells leads to activation of CK2, which in turn promotes cell survival by either direct negative regulation of proapoptotic proteins such as Bid or by inducing expression of antiapoptotic proteins such as Bcl-2 and Bcl-xL (18). The mechanism of action of CD5-Fc proposed in this study differs from CTLA4-Fc where protection is most likely a result of blockade in costimulation (20, 21). This study suggests a novel function for CD5 in regulation of survival of activated T cells. As we report here, selectively eliminating activated T cells by targeting CD5 offers an opportunity for treatment of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.


   Acknowledgments
 
We thank Dr. James George for critical review of this manuscript, Drs. Wei-Min Luo and Tong Zhou for technical advice related to generation of recombinant adenovirus, and Glayne Axtell for help writing this 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 (AG16221) to C.R. and (T32 AI07051) to R.C.A. and a grant from the National Multiple Sclerosis Society (RG-3216-A-5) to S.R.B. Back

2 Address correspondence and reprint requests to Dr. Chander Raman, Department of Medicine, University of Alabama at Birmingham, LHRB 463, 1530 3rd Avenue South, Birmingham, AL 35294-0007. E-mail address: craman{at}uab.edu Back

3 Abbreviations used in this paper: EAE, experimental autoimmune encephalomyelitis; MOG, myelin oligodendrocyte glycoprotein; DLN, draining lymph node; SEB, staphylococcal enterotoxin B; WT, wild type; 7-AAD, 7-aminoactinomycin D; DiOC6, dihexyloxacarbocyanine; Ad-mCD5Fc, adenovirus encoding murine CD5Fc; Ad-hCD5Fc, adenovirus encoding human CD5Fc; AICD, activation-induced cell death. Back

Received for publication March 15, 2004. Accepted for publication July 14, 2004.


   References
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 Introduction
 Materials and Methods
 Results and Discussion
 References
 

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