Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8<sup>+</sup>Cytotoxic T Cells

Getts, Meghann Teague; Kim, Byung S.; Miller, Stephen D.

doi:10.1128/jvi.00008-07

Cited by 18 publications

(23 citation statements)

References 44 publications

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“…1A), nor did the D b -VP2 tetramer react with CNS cells from mice with myelin oligodendrocyte glycoprotein-induced EAE (data not shown). As shown previously (17,60), the proportion of virus-specific CD8 ϩ T cells was 7-to 10-fold higher in the CNS than in the spleen. Greater than 80% of the CNS-infiltrating CD8 ϩ T cells and greater than 10% of the splenic CD8 ϩ T cells from infected mice reacted to D b -VP2 tetramers, while approximately one-half of the D b -VP2 tetramer-positive cells produced IFN-␥.…”

Section: V␤6-bearing Viral Antigen-specific Cd8supporting

confidence: 81%

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Kang

Kim

2010

J Virol

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Induction of antigen-specific CD8؉ T cells bearing a high-avidity T-cell receptor (TCR) is thought to be an important factor in antiviral and antitumor immune responses. However, the relationship between TCR diversity and functional avidity of epitope-specific CD8 ؉ T cells accumulating in the central nervous system (CNS) during viral infection is unknown. Hence, analysis of T-cell diversity at the clonal level is important to understand the fate and function of virus-specific CD8 ؉ T cells. In this study, we examined the V␤ diversity and avidity of CD8 ؉ T cells specific to the predominant epitope (VP2 121-130 ) of Theiler's murine encephalomyelitis virus. We found that V␤6 ؉ CD8 ؉ T cells, associated with epitope specificity, predominantly expanded in the CNS during viral infection. Further investigations of antigen-specific V␤6 ؉ CD8 ؉ T cells by CDR3 spectratyping and sequencing indicated that distinct T-cell clonotypes are preferentially increased in the CNS compared to the periphery. Among the epitope-specific V␤6 ؉ CD8 ؉ T cells, MGX-J␤1.1 motif-bearing cells, which could be found at a high precursor frequency in naïve mice, were expanded in the CNS and tightly associated with gamma interferon production. These T cells displayed moderate avidity for the cognate epitope rather than the high avidity normally observed in memory/effector T cells. Therefore, our findings provide new insights into the CD8 ؉ T-cell repertoire during immune responses to viral infection in the CNS.

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Section: V␤6-bearing Viral Antigen-specific Cd8supporting

confidence: 81%

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Kang

Kim

2010

J Virol

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“…Mice were subcutaneously immunized 7 days prior to intracerebral viral infection near the base of the tail with 25 g of mixture of peptides representing three predominant capsid epitopes (VP1 233-250 , VP2 74-86 , and VP3 [24][25][26][27][28][29][30][31][32][33][34][35][36][37] ) or noncapsid epitopes (3D [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] , 3D [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] , and 3D 412-430 ), which were emulsified 1:1 in complete Freund adjuvant (CFA; Difco, Detroit, MI).…”

Section: Animalsmentioning

confidence: 99%

“…To induce specific immune suppression, ECDI [1-ethyl-3-(3-dimethyl-aminopropyl)-carbodiimide HCl]-mediated peptide-conjugated splenocytes were prepared as previously described (12,20,36). After removal of red blood cells by treatment with Tris-NH 4 Cl, splenocytes from naive SJL mice (3 ϫ 10 8 cells/ml) were conjugated with the mixtures of capsid or noncapsid peptides (1 mg/ml) for 1 h at 0°C in the presence of 30 mg of ECDI (Calbiochem, La Jolla, CA)/ml.…”

Section: Animalsmentioning

confidence: 99%

“…Our results indicate that a single predominant epitope region (3D [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ) is responsible for the majority of CD4 ϩ T-cell activation. Minor populations of CD4 ϩ T cells were stimulated with 2C 81-100 , 3D [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] , 3D 163-180 , and 3D 411-430 regions. Interestingly, the proportion of CNSinfiltrating CD4 ϩ T cells reactive to noncapsid epitopes in TMEV-infected SJL mice was as many as sixfold greater than those reactive to the major capsid epitopes (VP1 233-250 , VP2 [74][75][76][77][78][79][80][81][82][83][84][85][86] , and VP3 [24][25][26][27][28][29]…”

Section: Cd4mentioning

confidence: 99%

“…The majority of CNS-infiltrating CD8 ϩ T cells (50 to 70%) from B6 mice recognize VP2 121-130 (3,7), while two minor populations (Ͻ10%) react with VP2 165-173 and VP3 110-120 capsid epitopes (28). Similarly, three capsid epitopes recognized by CNS-infiltrating CD8 ϩ T cells of virus-infected SJL mice were identified (17); i.e., VP3 159-166 , VP3 [173][174][175][176][177][178][179][180][181] , and VP1 [11][12][13][14][15][16][17][18][19][20] . However, the overall magnitude of a CD8 ϩ T-cell response is threefold lower in susceptible SJL mice than in resistant B6 mice at the peak of virus-specific immune responses (29).…”

mentioning

confidence: 99%

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Theiler's Virus Infection Induces a Predominant Pathogenic CD4⁺T Cell Response to RNA Polymerase in Susceptible SJL/J Mice

Jin

Kang

Kim

2009

J Virol

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Theiler's murine encephalomyelitis virus (TMEV)-induced immune-mediated demyelinating disease in susceptible mouse strains has been extensively investigated as a relevant model for human multiple sclerosis. Previous investigations of antiviral T-cell responses focus on immune responses to viral capsid proteins, while virtually nothing is reported on immune responses to nonstructural proteins. In this study, we have identified noncapsid regions recognized by CD4؉ T cells from TMEV-infected mice using an overlapping peptide library. Interestingly, a greater number of CD4 ؉ T cells recognizing an epitope (3D 21-36 ) of the 3D viral RNA polymerase, in contrast to capsid epitopes, were detected in the CNS of TMEV-infected SJL mice, whereas only a minor population of CD4 ؉ T cells from infected C57BL/6 mice recognized this region. The effects of preimmunization and tolerization with these epitopes on the development of demyelinating disease indicated that capsid-specific CD4 ؉ T cells are protective during the early stages of viral infection, whereas 3D 21-36 -specific CD4؉ T cells exacerbate disease development. Therefore, protective versus pathogenic CD4 ؉ T-cell responses directed to TMEV appear to be epitope dependent, and the differences in CD4؉ T-cell responses to these epitopes between susceptible and resistant mice may play an important role in the resistance or susceptibility to virally induced demyelinating disease.Although the cause of human multiple sclerosis (MS) is unknown, one or multiple infectious agents may be involved in the initial infliction of tissue damage leading to autoimmunity. A possible viral association with MS is suggested by epidemiological studies (1,8,44), as well as the detection of viral antigens and virus-specific antibodies in the majority of MS patients (44). Intracerebral infection of the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains induces a progressive demyelinating disease that is similar to a form of MS (25). In addition, various immunological and genetic factors that affect the disease outcome in TMEV-infected mice closely parallel those associated with the development of MS (22). Furthermore, recent studies suggest that TMEV is an emerging human viral group (6, 24). Therefore, TMEV-induced demyelinating disease (TMEV-IDD) is an attractive and relevant infectious model for studying the underlying mechanisms of MS.Previous immunological studies with susceptible SJL mice suggested that a Th1 response to viral capsid proteins is involved in the pathogenesis of demyelination (19,36,49,50). The major population of Th cells specific for TMEV during the course of disease essentially recognizes three predominant viral epitopes (VP1 233-250 , VP2 [74][75][76][77][78][79][80][81][82][83][84][85][86] , and VP3 24-37 ), one each on the external capsid proteins (11,48,49). However, a recent study indicated that Ͻ4% of the CD4 ϩ T cells in the central nervous systems (CNS) of TMEV-infected susceptible SJL/J (SJL) mice are reactive to viral ...

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Targeting the B7 Family of Co-Stimulatory Molecules

Podojil

Miller

2012

BioDrugs

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As more patient data is cross-referenced with animal models of disease, the primary focus on Th1 auto-reactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of Th17 autoreactive effector cells and the ability of regulatory T cells (Treg) to modulate the pro-inflammatory autoimmune response. Therefore, the currently favored hypothesis is that a delicate balance between Th1/17 effector cells and Treg cell function is critical in the regulation of inflammatory autoimmune disease. An intensive area of research with regard to the Th1/17:Treg cell balance is the utilization of blockade and/ or ligation of various co-stimulatory or co-inhibitory molecules, respectively, during ongoing disease to skew the immune response toward a more tolerogenic/regulatory state. Currently, FDA-approved therapies for multiple sclerosis patients are all aimed at the suppression of immune cell function. The other favored method of treatment is a modulation or deletion of autoreactive immune cells via short-term blockade of activating co-stimulatory receptors via treatment with fusion proteins such as CTLA4-Ig and CTLA4-FasL. Based on the initial success of CTLA4-Ig, there are additional fusion proteins that are currently under development. Examples of the more recently identified B7/CD28 family members are PD-L1, PD-L2, inducible co-stimulatory molecule-ligand (ICOS-L), B7-H3, and B7-H4, all of which may emerge as potential fusion protein therapeutics, each with unique, yet often overlapping functions. The expression of both stimulatory and inhibitory B7 molecules seems to play an essential role in modulating immune cell function through a variety of mechanisms, which is supported by findings that suggest each B7 molecule has developed its own indispensable niche in the immune system. As more data are generated, the diagnostic and therapeutic potential of the above B7 family-member-derived fusion proteins becomes ever more apparent. Besides defining the biology of these B7/CD28 family members in vivo, additional difficulty in the development of these therapies lies in maintaining the normal immune functions of recognition and reaction to non-self-antigens following viral or bacterial infection in the patient. Further complicating the clinical translation of these therapies, the mechanism of action identified for a particular reagent may depend upon the method of immune-cell activation and the subset of immune cells targeted in the study.

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Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8⁺Cytotoxic T Cells

Cited by 18 publications

References 44 publications

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Theiler's Virus Infection Induces a Predominant Pathogenic CD4⁺T Cell Response to RNA Polymerase in Susceptible SJL/J Mice

Targeting the B7 Family of Co-Stimulatory Molecules

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Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8+Cytotoxic T Cells

Cited by 18 publications

References 44 publications

Predominant Clonal Accumulation of CD8+T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Predominant Clonal Accumulation of CD8+T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Theiler's Virus Infection Induces a Predominant Pathogenic CD4+T Cell Response to RNA Polymerase in Susceptible SJL/J Mice

Targeting the B7 Family of Co-Stimulatory Molecules

Contact Info

Product

Resources

About

Differential Outcome of Tolerance Induction in Naive versus Activated Theiler's Virus Epitope-Specific CD8⁺Cytotoxic T Cells

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Predominant Clonal Accumulation of CD8⁺T Cells with Moderate Avidity in the Central Nervous Systems of Theiler's Virus-Infected C57BL/6 Mice

Theiler's Virus Infection Induces a Predominant Pathogenic CD4⁺T Cell Response to RNA Polymerase in Susceptible SJL/J Mice