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Journal of Virology, November 2002, p. 10785-10790, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10785-10790.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

V4⁺ T Cells Promote Autoimmune CD8⁺ Cytolytic T-Lymphocyte Activation in Coxsackievirus B3-Induced Myocarditis in Mice: Role for CD4⁺ Th1 Cells

Department of Pathology, University of Vermont, Burlington, Vermont,¹ Beth Israel Deaconess Medical Center, Boston, Massachusetts²

Received 17 May 2002/ Accepted 5 August 2002

	ABSTRACT

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T cells expressing the V4 T-cell receptor (TCR) promote myocarditis in coxsackievirus B3 (CVB3)-infected BALB/c mice. CD1, a major histocompatibility complex (MHC) class I-like molecule, is required for activation of V4⁺ cells. Once activated, V4⁺ cells initiate myocarditis through gamma interferon (IFN-)-mediated induction of CD4⁺ T helper type 1 (Th1) cells in the infected animal. These CD4⁺ Th1 cells are required for activation of an autoimmune CD8⁺ ß TCR⁺ effector, which is the predominant pathogenic agent in this model of CVB3-induced myocarditis. Activated V4⁺ cells can adoptively transfer myocarditis into BALB/c mice infected with a nonmyocarditic variant of CVB3 (H310A1) but cannot transfer myocarditis into either uninfected or CD1^-/- recipients, demonstrating the need for both infection and CD1 expression for V4⁺ cell function. In contrast, CD8⁺ ß TCR⁺ cells transfer myocarditis into either infected CD1^-/- or uninfected recipients, showing that once activated, the CD8⁺ ß TCR⁺ effectors function independently of both virus and CD1. V4⁺ cells given to mice lacking CD4⁺ T cells minimally activate the CD8⁺ ß TCR⁺ cells. These studies show that V4⁺ cells determine CVB3 pathogenicity by their ability to influence both the CD4⁺ and CD8⁺ adaptive immune response. V4⁺ cells enhance CD4⁺ Th1 (IFN-⁺) cell activation through IFN-- and CD1-dependent mechanisms. CD4⁺ Th1 cells promote activation of the autoimmune CD8⁺ ß TCR⁺ effectors.

	INTRODUCTION

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Myocarditis is an inflammation of the myocardium, and it often follows microbial infections (23). Enteroviruses are most frequently implicated in this disease (7). The virus may be directly pathogenic to cardiac myocytes, either by direct lysis of the cells during the virus replication cycle (29), disruption of cardiac myocyte function (30), or induction of locally produced proinflammatory cytokines which suppress myocyte contractility (4). Enteroviruses may also establish persistent infections in the heart, and these persistently infected cardiocytes may be dysfunctional (17). Nonetheless, presumably such injury would be largely restricted to infected cardiocytes. If the number of infected myocytes in the heart is small, then damage directly attributable to the virus would be minimal and may not produce clinical disease.

Either virus-specific or autoimmune responses also contribute to myocarditis. T-cell-deficient mice develop minimal cardiac injury despite high virus titers in the heart (31). Three distinct types of T-cell responses have been found in coxsackievirus B3 (CVB3)-induced myocarditis. These are lymphocytes expressing the V4 T-cell receptor (TCR) (8), CD4⁺ Th1 (gamma interferon [IFN-] positive) (8, 9), and CD8⁺ ß TCR⁺ autoimmune cytolytic T lymphocytes (CTL) (10, 11). Evidence to date strongly indicates that the autoimmune CD8⁺ ß TCR⁺ CTL is the major mediator of cardiac damage. However, the activation of the CD8⁺ ß TCR⁺ CTL is complex and poorly understood. A nonmyocarditic CVB3 variant (H310A1), which differs from the myocarditic variant (H3) by a single amino acid in the VP2 capsid protein, fails to activate any of the three T-cell types listed above (8, 12, 18). The key deficiency seems to be the lack of a V4⁺ T-cell response, since adoptive transfer of activated V4⁺ cells from H3 virus-infected donors into H310A1 virus-infected recipients completely restores myocarditis susceptibility (8) and, as shown here, a CD8⁺ ß TCR⁺ CTL response. One key difference between H3 and H310A1 virus infections in the heart is that the myocarditic H3 virus induces expression of CD1d but the H310A1 virus does not (S. A. Huber, unpublished observations). CD1 is a nonpolymorphic cell-surface glycoprotein with structural homology to major histocompatibility complex (MHC) class I molecules (2, 24, 27). The studies presented here hypothesize that CD1d is important in myocarditis susceptibility in vivo because this antigen is necessary for V4⁺ T-cell activation. In turn, the V4⁺ T cells promote activation of CD4⁺ Th1 cells that are necessary for CD8⁺ ß TCR⁺ effector cell responses. Although the CD8⁺ ß TCR⁺ effector cell is the ultimate pathogenic agent, activation of these cells is a complex process involving both early innate (V4⁺ T cell) and adaptive (CD4⁺ Th1 cell) immunity.

	MATERIALS AND METHODS

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Mice. Male mice, 5 to 6 weeks of age, were used in these experiments. BALB/cJ, BALB/c-Il4ra tm1Sz (interleukin-4 [IL-4] knockout), and C.129S7(B6)-Ifngtm1Ts (IFN- knockout) mice were purchased from Jackson Laboratories, Bar Harbor, Maine. Breeding pairs of BALB/c CD1 mice were originally obtained from Michael J. Grusby, Harvard School of Public Health, Boston, Mass.

Virus, virus infection, and virus titration. Animals were infected by intraperitoneal (i.p.) injection of 0.5 ml of phosphate-buffered saline (PBS) containing 10⁴ PFU of either CVB3 H3 (myocarditic) or H310A1 (nonmyocarditic) variants as described previously (8).

Antibodies. Antibody class control (isotype control) and antigen-specific antibodies were obtained from Pharmingen (San Diego, Calif.). These included biotinylated and phycoerythrin (PE)-conjugated anti-CD3 (clone 17A2); PE-conjugated anti-TCRß (clone H57-597); purified rat anti-mouse CD16/CD32 (Fc Block; clone 2.4G2); biotinylated, Cy-Chrome-, fluorescein isothiocyanate (FITC)-, and PE-conjugated rat immunoglobulin G1 (IgG1) (clone R3-34); FITC-conjugated anti-mouse IFN- (clone XMG 1.2); PE-conjugated rat anti-mouse IL-4 (clone BVD4-1D11); Cy-Chrome-conjugated rat anti-mouse CD4 (clone GK 1.5); purified anti-hamster IgG cocktail (clones G70-204/G94-56); FITC-conjugated rat anti-mouse CD8ß (clone 53-5.8); PE-coinjugated hamster anti-mouse CD69 (clone H1.2F3); purified anti-mouse IAd (clone 39-10-8); purified anti- TCR (clone GL3); and purified, FITC-conjugated anti-V4 (clone UC3).

Isolation of splenic lymphocytes. Isolation of cell populations has been described previously (8). CD8⁺ or V4⁺ cells were isolated by depleting splenocytes of CD4⁺ cells, macrophages, and B lymphocytes by using anti-CD4 and anti-IAd monoclonal antibodies, then incubating the cells with anti-rat IgG and anti-mouse IgG-conjugated magnetic particles (PerSeptive Biosystems, Framingham, Mass.), followed by staining cells with either 1:50 dilutions of FITC-anti-CD8 and PE-anti-ß TCR, or with FITC-anti-V4 and PE-anti-CD3 for 20 min on ice, washing, resuspending the cells in RPMI 1640 containing 10% fetal bovine serum (Life Technologies), and sterile sorting the double-positive cell populations.

Isolation of neonatal myocytes. Isolation of neonatal mouse myocytes has been described previously (10). Briefly, hearts were obtained from mice within 72 h of birth, minced finely, and subjected to sequential digestion with 0.25% pancreatin (GIBCO) and 0.4% collagenase (Worthington Biochemical Co., Freehold, N.J.). The single-cell suspension was washed and depleted of endothelial cells and fibroblasts by two sequential 1-h adsorptions to plastic. The nonadherent population was retrieved and plated into 1-mm tissue culture wells (Falcon) at 10³ cells/well. After 48 h at 37°C in a humidified 5% CO₂ incubator, the wells were used for cytotoxicity assays.

CMC assay. The cell-mediated cytotoxicity (CMC) assay has been described in detail previously (10). Targets were labeled with 100 µCi of ⁵¹Cr (Na₂⁵¹CrO₄; ICN, Irvine, Calif.) for 2 h at 37°C, washed four times, and cultured for 12 h at 37°C with 10⁴ lymphocytes (effector/target ratio of 10:1). Supernatants were removed and counted in a Packard gamma counter (Downers Grove, Ill.). Pellets were lysed using 6 N HCl, and the pellets were removed and counted. To determine maximal releasable ⁵¹Cr, some wells were directly treated with HCl to lyse all targets. The percent ⁵¹Cr release was calculated for each well as follows: [(CPM in supernatant)/(CPM in supernatant + CPM in pellet)] x 100. The percent specific lysis was calculated as follows: [(percent ⁵¹Cr release in experimental wells - percent ⁵¹Cr release in medium control wells)/(percent ⁵¹Cr in HCl-lysed maximum release wells - percent ⁵¹Cr release in medium control wells)] x 100.

Flow cytometry. The detailed methods used for the flow cytometry have been reported previously (8). For staining cell surface markers, cells were incubated for 20 min in PBS-1% bovine serum albumin (BSA) containing 1:100 dilutions of FcBlock and fluorochome-labeled antibodies, washed once, and resuspended in 2% paraformaldehyde. For intracellular cytokine staining, cells were cultured in medium containing 10 µg of Brefeldin A/ml, 50 ng of phorbol myristate acetate/ml, and 500 ng of ionomycin (Sigma Chemical Co., St. Louis, Mo.)/ml for 4 h at 37°C in 5% CO₂, washed in PBS-1% BSA containing Brefeldin A, surface stained with Cy-Chrome-conjugated anti-CD4, washed again, fixed with 2% paraformaldehyde, resuspended in PBS-BSA buffer containing 0.5% saponin and 1:100 dilutions of FcBlock, FITC-anti-IFN-, and PE-anti-IL-4 for 30 min, washed once in PBS-BSA-saponin and once in saponin-free PBS-BSA, and then resuspended in 2% paraformaldehyde. Positive controls for cytokine staining were 2.5 x 10⁵ of either MIC-1 (IFN-) or MIC-2 (IL-4) fixed cells obtained from Pharmingen. Negative controls were fluorochrome-conjugated species- and isotype-matched immunoglobulins. Stained cell populations were analyzed using a Coulter Epics Elite instrument with a single excitation wavelength (488 nm) and band filters for PE (575 nm), FITC (525 nm), and Cy-Chrome (670 nm). Each sample population was classified for cell size (forward scatter) and complexity (side scatter) and then gated on a population of interest. At least 10,000 cells were evaluated for each sample. Criteria for positive staining were established using isotype controls.

Adoptive transfer of purified cell populations. V4⁺ and CD8 ß TCR⁺ cell populations were isolated as described above, washed, and resuspended in PBS to a concentration of 5 x 10⁴ (V4⁺) or 5 x 10⁵ (CD8 ß TCR⁺) cells/ml. Mice were injected intravenously (i.v.) through the tail vein with 0.2 ml of the cell suspension 2 days after recipients were infected with virus.

Histology. Hearts were removed, fixed in 10% buffered formalin, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Stained sections were evaluated for myocarditis as described previously (8).

Statistics. Statistical evaluation was performed using either the Wilcoxon ranked score method or the Student t test. Each experiment was repeated at least two times.

	RESULTS

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V4⁺ cell activity requires both IFN- and CD1. Previous studies (8) using Stat4^-/- mice indicated that IFN- produced by V4⁺ cells promotes myocarditis induction, since this transcription factor is involved in IFN- expression through its regulation of IL-12 (32). However, Stat4 might control expression of other genes besides IL-12, and some IFN- expression can be IL-12 independent. The following studies more directly investigate the role of IFN- in V4⁺ cell modulation of myocarditis susceptibility. First, BALB/c, BALB/c IL-4^-/-, and BALB/c IFN-^-/- mice were infected with H3 virus and evaluated for myocarditis, CD4⁺ Th phenotype, and cytokine expression by V4⁺ cells (Table 1). BALB/c and BALB/c IL-4^-/- mice develop myocarditis and CD4⁺ Th1 (IFN-⁺) cell responses, whereas BALB/c IFN-^-/- mice do not. V4⁺ cells, isolated from H3 virus-infected BALB/c mice, express IFN- but little IL-4 (8). V4⁺ cells from IFN-^-/- mice showed neither cytokine (Table 1). Next, V4⁺ T cells isolated by cell sorting from infected BALB/c, IL-4^-/-, and IFN-^-/- mice were adoptively transferred into either wild-type BALB/c recipients infected with the nonmyocarditic CVB3 variant (H310A1) (Table 1) or into BALB/c CD1^-/- recipients infected with the myocarditic H3 variant (Table 1). Seven days after infection of the recipients, peripheral blood lymphocytes were retrieved and evaluated by cell surface and intracellular staining for CD4⁺ cells producing IFN- and IL-4. Hearts were evaluated for myocarditis and cardiac virus titers. CD8⁺ ß TCR⁺ effectors were isolated with a fluorescence-activated cell sorter and assayed for cytotoxicity to uninfected BALB/c cardiac myocytes in a ⁵¹Cr release assay. Previously published studies have shown that adoptive transfer of ⁺ or V4⁺ cells from myocarditic mice restores myocarditis susceptibility in syngeneic animals infected with the H310A1 virus (8). This experiment demonstrates that restoration of disease susceptibility requires both IFN- expression by the V4⁺ cells and CD1 expression in the recipients. Recipients not given V4⁺ cells showed minimal cardiac inflammation, poor IFN- expression by peripheral blood CD4⁺ T cells, and poor CD8⁺ ß TCR⁺ effector function. Giving V4⁺ cells from BALB/c and BALB/c IL-4^-/- donors restored myocarditis susceptibility, CD4⁺ IFN- expression, and CD8⁺ ß TCR⁺ effector activity in wild-type BALB/c mice infected with the H310A1 virus but not in CD1^-/- recipients. V4⁺ cells from IFN-^-/- donors were incapable of restoring myocarditis in either wild-type (CD1⁺) or CD1^-/- recipients. These studies also show that CD8⁺ ß TCR⁺ CTL responses correlate with myocarditis susceptibility and only occur when V4⁺ cells promote CD4⁺ Th1 cell responses.

View this table: [in this window] [in a new window]   TABLE 1. V4+ cells promote myocarditis through IFN- expressiona

CD8⁺ ß TCR⁺ CTL adoptively transfer myocarditis in both wild-type and CD1^-/- recipients.

View this table: [in this window] [in a new window]   TABLE 2. Adoptive transfer CD8+ ß TCR+ effectors into BALB/c and CD1-/- recipientsa

View larger version (34K): [in this window] [in a new window]   FIG. 1. Effect of V4+ and CD8 ß TCR+ cell transfer on CD4+ Th phenotype. V4+ and CD8 ß TCR+ cells were isolated as described in Materials and Methods from H3 virus-infected BALB/c donor mice 7 days after infection. These cell populations were transferred into either uninfected BALB/c (uBALB/c), H310A1 virus-infected BALB/c (vBALB/c), or H3 virus-infected CD1-/- (vCD1-/-) recipients. Recipients were infected i.p. with virus and injected 2 days later i.v. through the tail vein with either 104 V4+ or 105 CD8 ß TCR+ cells. Recipients were killed 7 days after infection. Peripheral blood lymphocytes were retrieved, stimulated with phorbol myristate acetage, ionomycin, and Brefeldin A for 4 h, then stained for CD4, fixed, permeabilized, and intracellularly stained for IFN- and IL-4. Numbers in the upper right corner indicate the percentage of peripheral blood cells in each quadrant of a single mouse in each group.

Requirement of CD4⁺ cells for CD8⁺ ß TCR⁺ CTL activation.

View this table: [in this window] [in a new window]   TABLE 3. Adoptive transfer of V4+ cells into CD4+- and CD8+-cell depleted recipientsa

	DISCUSSION

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T cells expressing the TCR form a part of the innate immune system and are most frequently distributed in mucosal membranes, intestinal epithelium, and skin (5, 26). ⁺ cell numbers often increase at inflammatory sites and may play an important role in modulating the adaptive (ß TCR⁺ cell-dependent) immune response (5, 6, 19, 21, 22, 28). Previously, we have shown that ⁺ cells are important in determining susceptibility of mice to CVB3-induced myocarditis (8, 9, 12-15). Specifically, T cells expressing the V4⁺ TCR promote myocarditis susceptibility, whereas T cells expressing the V1 TCR cause myocarditis resistance (8, 15). Disease susceptibility always correlates with preferential activation of CD4⁺ Th1 (IFN-⁺) cells. The V4⁺ cells express high levels of IFN- and localize to the infected myocardium within 1 to 2 days of virus inoculation (S. A. Huber, unpublished). This rapid V4⁺ infiltration of the heart, and the ability of these cells to make IFN-, undoubtedly provides an environment conducive to CD4⁺ Th1 cell development. A major question is whether the V4⁺ cell modulation of the CD4⁺ T-cell response is important in disease development or represents an epiphenomenon.

CD8⁺ CTLs are the major pathogenic effectors in CVB3-induced myocarditis in BALB/c mice (10, 11). These are autoimmune CTL reacting to heart-specific antigens and killing cardiac myocytes but not other tissue-specific (noncardiac) targets. Furthermore, the CD8⁺ effectors can adoptively transfer myocarditis into uninfected syngeneic recipients. Preliminary data from this laboratory in collaboration with Kirk Knowlton (University of California, San Diego) and Madeleine Cunningham (University of Oklahoma) have recently identified an MHC class I Ld peptide in the 3D polymerase of the H3 variant which is recognized by both the CD8⁺ ß TCR⁺ effectors from H3 virus-infected BALB/c mice and by CD8⁺ ß TCR⁺ effectors isolated from BALB/c mice immunized with cardiac myosin (unpublished data). These results strongly indicate that autoimmunity results from antigenic mimicry between the virus and the target tissue. The nonpathogenic H310A1 variant has the identical Ld-restricted epitope, which means that the reason autoimmunity is not induced with this virus must reflect other factors preventing CD8⁺ ß TCR⁺ effector activation. We believe that a strong CD4⁺ Th1 cell response is crucial to providing the cytokine milieu and possibly the accessory-molecule expression (such as B7 antigen) necessary for CD8⁺ cell responses. Furthermore, H3 virus up-regulates CD1d expression in the heart, whereas H310A1 virus does not (S. A. Huber, unpublished observations). The crucial defect in H310A1 virus infections is that the lack of CD1 expression fails to activate V4⁺ cells required for CD8⁺ ß TCR⁺ cell stimulation to the cross-reactive epitope in the virus.

The ability of either V4⁺ or CD8⁺ ß TCR⁺ cells to transfer disease into uninfected recipient mice does not result from inadvertent transfer of virus, as recipients have no detectable virus and do not make anti-CVB3 antibodies and homogenates of the effector cells do not have infectious virus by the plaque forming assay. CD8⁺ ß TCR⁺ effectors kill both CD1^- and CD1⁺ myocytes equivalently, showing that these effectors do not require CD1-presented antigen on target cells (16). This is also shown as CD8⁺ ß TCR⁺ cells equivalently transfer myocarditis into both CD1^-/- and wild-type mice, whereas V4⁺ cells can only induce myocarditis and CD8⁺ ß TCR⁺ cell activation in CD1⁺ mice. Clearly, the activation of the CD8⁺ ß TCR⁺ effectors is CD1 antigen dependent, but their effector function is independent of CD1.

V4⁺ cells do not directly activate the CD8⁺ ß TCR⁺ cell population, since adoptive transfer of V4⁺ cells into mice made deficient of CD4⁺ cells promotes minimal myocarditis or CD8⁺ ß TCR⁺ CTL activity. Adoptive transfer of V4⁺ cells into recipients depleted of CD8⁺ cells allows generation of CD4⁺ Th1 cells, but without the CD8⁺ cell population no myocarditis is induced. This strongly implies that V4⁺ cells act through the CD4⁺ Th1 cell response in promoting CD8⁺ ß TCR⁺ CTL generation. CD4⁺ cells are known to moderate CD8⁺ CTL responses in two ways. CD4⁺ Th1 cells directly promote CD8⁺ effector cell responses through cytokine release (20), whereas IL-4, produced by CD4⁺ Th2 cells, can suppresses CD8⁺ ß TCR⁺ CTL generation (1, 3). Since up-regulation of CD4⁺ Th1 cell responses down-regulates CD4⁺ Th2 cell responses (25, 33), one might hypothesize that CD4⁺ Th1 cells promote CD8⁺ ß TCR⁺ CTL activation only by preventing the generation of regulatory CD4⁺ Th2 cells. It was somewhat surprising that CD8⁺ ß TCR⁺ cells did not promote CD4⁺ Th1 cell bias in vivo (3). Presumably, other environmental factors in the H310A1 virus-infected host prevent a CD4⁺ Th1 cell bias.

The mechanism by which V4⁺ cells modulate the CD4⁺ Th cell response is still under investigation. We have shown that ⁺ T cells in the myocardium of H3 virus-infected mice express high levels of FasL and are capable of specifically killing CD4⁺ Th2 cell clones through Fas-dependent mechanisms (16). We have also observed that Th0-like CD4⁺ T cells (IFN-⁺/IL-4⁺), in H3 virus-infected BALB/c mice, have murine CD1 (mCD1) on their cell surface as determined by flow analysis (S. A. Huber, unpublished observations). Although it is possible that a subpopulation of CD4⁺ T cells might inherently express CD1 protein, the more likely explanation is that these antigen-specific cells passively acquire the CD1 molecule during interactions with CD1⁺ antigen-presenting cells. However the CD1 molecule is obtained, CD1⁺ CD4⁺ T cells might directly interact with CD1-restricted V4⁺ cells. IFN- produced by the V4⁺ cells might then be highly effective in directing further CD4⁺-cell differentiation towards a Th1 phenotype.

	ACKNOWLEDGMENTS

 
We thank Steven P. Balk for suggestions and review of the manuscript and Michael Grusby for the BALB/c CD1^-/- mice. We thank Colette Charland for expert technical assistance with flow analysis and Debbie Perrotte for her help in preparation of the manuscript.

This work was supported by NIH grants HL 58583 and 1P01 AI45666-01 (S.A.H.) and CA89567 (M.E.).

	FOOTNOTES

 
* Corresponding author. Mailing address: University of Vermont, Department of Pathology, 208 S. Park Drive, Suite 2, Colchester, VT 05446. Phone: (802) 656-8944. Fax: (802) 656-8965. E-mail: Sally.Huber{at}uvm.edu.

	REFERENCES

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Bot, A., A. Holz, U. Christen, T. Wolfe, A. Temann, R. Flavell, and M. von Herrath. 2000. Local IL-4 expression in the lung reduces pulmonary influenza-virus-specific secondary cytotoxic T cell responses. Virology 269:66-77.[CrossRef][Medline]
2. Exley, M., S. Porcelli, M. Furman, J. Garcia, and S. Balk. 1998. CD161 (NKR-P1A) costimulation of CD1d-dependent activation of human T cells expressing the invariant V 24J Q T cell receptor alpha chains. J. Exp. Med. 188:867-876.[Abstract/Free Full Text]
3. Fitch, F. W., M. D. McKisic, D. W. Lancki, and T. F. Gajewski. 1993. Differential regulation of T lymphocyte subsets. Annu. Rev. Immunol. 11:29-48.[CrossRef][Medline]
4. Freeman, G. L., J. T. Colson, M. Zabalgoitia, and B. Chandrasekar. 1998. Contractile depression and expression of proinflammatory cytokines and iNOS in viral myocarditis. Am. J. Physiol. 274:H249-H258.
5. Hayday, A. 2000. Gamma-delta cells: a right time and a right place for a conserved third way of protection. Annu. Rev. Immunol. 18:975-1026.[CrossRef][Medline]
6. Holt, P. 1996. Immunoregulation of the allergic reaction in the respiratory tract. Eur. Resp. J. 22:85S-89S.
7. Huber, S. A., C. J. Gauntt, and P. Sakkinen. 1998. Enteroviruses and myocarditis: viral pathogenesis through replication, cytokine induction and immunopathogenicity. Adv. Virus Res. 51:35-80.[Medline]
8. Huber, S. A., D. Graveline, W. K. Born, and R. L. O'Brien. 2001. Cytokine production by V⁺-T-cell subsets is an important factor determining CD4⁺-Th-cell phenotype and susceptibility of BALB/c mice to coxsackievirus B3-induced myocarditis. J. Virol. 75:5860-5868.[Abstract/Free Full Text]
9. Huber, S. A., A. Mortensen, and G. Moulton. 1996. Modulation of cytokine expression by CD4⁺ T cells during coxsackievirus B3 infections of BALB/c mice by cells expressing the ⁺ T-cell receptor. J. Virol. 70:3039-3045.[Abstract]
10. Huber, S. A., and P. Lodge. 1984. Coxsackievirus B3 myocarditis in Balb/c mice: evidence for autoimmunity to myocyte antigens. Am. J. Pathol. 116:21.[Abstract]
11. Huber, S. A., et al. 1987. The role of T lymphocytes in the pathogenesis of coxsackievirus B3 myocarditis, p. 9-21. In C. Kawai, W. Abelmann, and A. Matsumori (ed.), Cardiomyopathy update 1: pathogenesis of myocarditis and cardiomyopathy. University of Tokyo Press, Tokyo, Japan.
12. Huber, S. A., J. Polgar, P. Schultheiss, and P. Schwimmbeck. 1994. Augmentation of pathogenesis of coxsackievirus B3 infections in mice by exogenous administration of interleukin-1 and interleukin-2. J. Virol. 68:195-206.[Abstract/Free Full Text]
13. Huber, S. A., A. Moraska, and M. Choate. 1992. T cells expressing the T-cell receptor potentiate coxsackievirus B3-induced myocarditis. J. Virol. 66:6541-6546.[Abstract/Free Full Text]
14. Huber, S. A., J. Kupperman, and M. Newell. 1999. Hormonal regulation of CD4⁺ T-cell responses in coxsackievirus B3-induced myocarditis in mice. J. Virol. 73:4689-4695.[Abstract/Free Full Text]
15. Huber, S. A., D. Graveline, M. K. Newell, W. K. Born, and R. L. O'Brien. 2000. V1⁺ T cells suppress and V4⁺ T cells promote susceptibility to coxsackievirus B3-induced myocarditis in mice. J. Immunol. 165:4174-4181.[Abstract/Free Full Text]
16. Huber, S. A., C. Shi, and R. C. Budd. 2002. T cells promote a Th1 response during coxsackievirus B3 infection in vivo: role of Fas and Fas⁺ ligand. J. Virol. 76:6487-6494.[Abstract/Free Full Text]
17. Kandolf, R., M. Sauter, C. Aepinus, J. J. Schnorr, H. C. Selinka, and K. Klingel. 1999. Mechanisms and consequences of enterovirus persistence in cardiac myocytes and cells of the immune system. Virus Res. 62:149-158.[CrossRef][Medline]
18. Knowlton, K. U., E. S. Jeon, N. Berkley, R. Wessely, and S. Huber. 1996. A mutation in the puff region of VP2 attenuates the myocarditic phenotype of an infectious cDNA of the Woodruff variant of coxsackievirus B3. J. Virol. 70:7811-7818.[Abstract]
19. Lahn, M. 2000. The role of gammadelta T cells in the airways. J. Mol. Med. 76:409-425.
20. Lopex-Dias de Cerio, A. L., N. Casares, J. J. Lasarte, P. Sarobe, L. A. Perez-Mediavilla, M. Ruiz, J. Prieto, and F. Borras-Cuesta. 1999. T(h)1 but not T(h)0 cell help is efficient to induce cytotoxic T lymphocytes by immunization with short synthetic peptides. Int. Immunol. 11:2025-2034.[Abstract/Free Full Text]
21. McMenamin, C., C. Pimm, M. McKersey, and P. G. Holt.1994. Regulation of IgE responses to inhaled antigen in mice by antigen-specific ⁺ T cells. Science 265:1869-1873.[Abstract/Free Full Text]
22. O'Brien, R., M. Lahn, W. K. Born, and S. A. Huber. 2001. T cell receptor and function cosegregate in gamma-delta T cell subsets. Chem. Immunol. 79:1-28.[Medline]
23. Olsen, E. 1985. What is myocarditis?, p. 1-3. In E.O. M. Sekiguchi and J. F. Goodwin (ed.), Myocarditis and related disorders. Springer-Verlag, Tokyo, Japan.
24. Porcelli, S. 1995. The CD1 family: a third lineage of antigen-presenting molecules. Adv. Immunol. 59:1-98.[Medline]
25. Ray, A., and L. Cohn. 2000. Altering the Th1/Th2 balance as a therapeutic strategy in asthmatic diseases. Curr. Opin. Investig. Drugs 1:442-448.[Medline]
26. Salerno, A., and F. Dieli. 1998. Role of gamma delta T lymphocytes in immune response in humans and mice. Crit. Rev. Immunol. 18:327-357.[Medline]
27. Sieling, P. 2000. CD1-restricted T cells: T cells with a unique immunological niche. Clin. Immunol. 96:3-10.[CrossRef][Medline]
28. Vincent, M. S., K. Roessner, D. Lynch, D. Wilson, S. M. Cooper, J. Tschopp, L. H. Sigal, and R. C. Budd. 1996. Apoptosis of Fas^high CD4⁺ synovial T cells by Borrelia-reactive Fas-ligand(high) gamma delta T cells in Lyme arthritis. J. Exp. Med. 184:2109-2117.[Abstract/Free Full Text]
29. Wessely, R., A. Henke, R. Zell, R. Kandolf, and K. U. Knowlton. 1998. Low-level expression of a mutant coxsackieviral cDNA induces a myocytopathic effect in culture: an approach to the study of enteroviral persistence in cardiac myocytes. Circulation 98:450-457.[Abstract/Free Full Text]
30. Wessely, R., K. Klingel, L. F. Santana, N. Dalton, M. Hongo, W. J. Lederer, R. Kandolf, and K. U. Knowlton. 1998. Transgenic expression of replication-restricted enteroviral genomes in heart muscle induces defective excitation-contraction coupling and dilated cardiomyopathy. J. Clin. Investig. 102:1444-1453.[Medline]
31. Woodruff, J., and J. Woodruff. 1974. Involvement of T lymphocytes in the pathogenesis of coxsackievirus B3 heart disease. J. Immunol. 113:1726-1734.[Abstract/Free Full Text]
32. Wurster, A., T. Tanaka, and M. Grusby. 2000. The biology of Stat4 and Stat6. Oncogene 19:2577-2584.[CrossRef][Medline]
33. Zelenika, D., E. Adams, S. Humm, L. Graca, S. Thompson, S. P. Cobbold, and H. Waldmann. 2002. Regulatory T cells overexpress a subset of Th2 gene transcripts. J. Immunol. 168:1069-1079.[Abstract/Free Full Text]

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