LCMV-Specific, Class II-Restricted Cytotoxic T Cells in β2-Microglobulin-Deficient Mice

Müller, Daniel; Koller, BH; Whitton, J. Lindsay; LaPan, KE; Brigman, KK; Frelinger, J. A.

doi:10.1126/science.1347959

Cited by 157 publications

(114 citation statements)

References 30 publications

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“…BAL from all three vaccinated groups were tested for their ability to lyse Sendai virus-infected L-I-A b target on day 10 after infection (data not shown). No cytolytic activity was detected, consistent with the finding that MHC class II-restricted CD4 ϩ CTL activity is usually not detectable in mice with an intact immune system (7,33).…”

Section: Priming With the Hn 421-436 Cd4 ϩ T Cell Epitope Alters The supporting

confidence: 71%

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CD4+ T Cell Priming Accelerates the Clearance of Sendai Virus in Mice, but Has a Negative Effect on CD8+ T Cell Memory

Zhong

Marshall

Coleclough

et al. 2000

The Journal of Immunology

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Current vaccines designed to promote humoral immunity to respiratory virus infections also induce potent CD4+ T cell memory. However, little is known about the impact of primed CD4+ T cells on the immune response to heterologous viruses that are serologically distinct, but that share CD4+ T cell epitopes. In addition, the protective capacity of primed CD4+ T cells has not been fully evaluated. In the present study, we addressed these two issues using a murine Sendai virus model. Mice were primed with an HN421–436 peptide that represents the dominant CD4+ T cell epitope on the hemagglutinin-neuraminidase (HN) of Sendai virus. This vaccination strategy induced strong CD4+ T cell memory to the peptide, but did not induce Abs specific for the Sendai virus virion. Subsequent Sendai virus infection of primed mice resulted in 1) a substantially accelerated virus-specific CD4+ T cell response in the pneumonic lung; 2) enhanced primary antiviral Ab-forming cell response in the mediastinal lymph nodes; and 3) accelerated viral clearance. Interestingly, the virus-specific CD8+ T cell response in the lung and the development of long-term memory CD8+ T cells in the spleen were significantly reduced. Taken together, our data demonstrate that primed CD4+ T cells, in the absence of pre-existing Ab, can have a significant effect on the subsequent immune responses to a respiratory virus infection.

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Section: Priming With the Hn 421-436 Cd4 ϩ T Cell Epitope Alters The supporting

confidence: 71%

“…ϩ CTL activity has been detected in mice deficient in CD8 ϩ T cell function (7,33). Therefore, we also asked whether the CD4 ϩ T cells elicited by Sendai virus in HN 421-436 peptidevaccinated mice expressed in vitro cytotoxic activity.…”

Section: Priming With the Hn 421-436 Cd4 ϩ T Cell Epitope Alters The mentioning

confidence: 99%

CD4+ T Cell Priming Accelerates the Clearance of Sendai Virus in Mice, but Has a Negative Effect on CD8+ T Cell Memory

Zhong

Marshall

Coleclough

et al. 2000

The Journal of Immunology

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“…In contrast, mice lacking ␤ 2 -microglobulin (B 2 m) that exhibit a profound decrease in their numbers of CD8 T cells have partial and delayed mortality after intracranial LCMV infection and suffer from a wasting disease (28). This disease is similar to that seen in vvGimmunized mice after RSV challenge and results in weight loss, malaise, and ruffled fur (28). Adoptive transfer of purified CD4 T cells from LCMV-infected, ␤ 2 m-deficient mice can induce wasting disease in naive ␤ 2 m-deficient recipient mice (29).…”

Section: Discussionmentioning

confidence: 99%

“…In this model, intracranial infection with LCMV results in rapid mortality in immune-sufficient mice (26,27). In contrast, mice lacking ␤ 2 -microglobulin (B 2 m) that exhibit a profound decrease in their numbers of CD8 T cells have partial and delayed mortality after intracranial LCMV infection and suffer from a wasting disease (28). This disease is similar to that seen in vvGimmunized mice after RSV challenge and results in weight loss, malaise, and ruffled fur (28).…”

Section: Discussionmentioning

confidence: 99%

CD8 T Cells Inhibit Respiratory Syncytial Virus (RSV) Vaccine-Enhanced Disease

Olson

Varga

2007

The Journal of Immunology

105

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Vaccination of children with a formalin-inactivated (FI) respiratory syncytial virus (RSV) vaccine led to exacerbated disease including pulmonary eosinophilia following a natural RSV infection. Immunization of BALB/c mice with FI-RSV or a recombinant vaccinia virus (vv) expressing the RSV attachment (G) protein (vvG) results in a pulmonary Th2 response and eosinophilia after RSV challenge that closely mimics the RSV vaccine-enhanced disease observed in humans. The underlying causes of RSV vaccine-enhanced disease remain poorly understood. We demonstrate here that RSV M2-specific CD8 T cells reduce the Th2-mediated pathology induced by vvG-immunization and RSV challenge in an IFN-γ-independent manner. We also demonstrate that FI-RSV immunization does not induce a measurable RSV-specific CD8 T cell response and that priming FI-RSV-immunized mice for a potent memory RSV-specific CD8 T cell response abrogates pulmonary eosinophilia after subsequent RSV challenge. Our results suggest that the failure of the FI-RSV vaccine to induce a CD8 T cell response may have contributed to the development of pulmonary eosinophilia and augmented disease that occurred in vaccinated individuals.

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“…Expression of MHC class I is considered instrumental in thymic education of MHC class I-restricted CD8+ CTLs and many studies have supported this view (7,8). It was reported that gene-targeted disruption of 2m results in the virtual disappearance of surface-expressed native MHC class I antigens and that 2m-deficient (/2m -/-) animals lack functional CD8+ CTLs (9)(10)(11)(12). A very low percentage of or no CD8+CD4-cells were found in the thymus or periphery of (2m -/-mice with no significant effect on the development or survival of such animals, raising doubts about the functional significance of CD8+ CTLs.…”

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confidence: 99%

Highly lytic CD8+, alpha beta T-cell receptor cytotoxic T cells with major histocompatibility complex (MHC) class I antigen-directed cytotoxicity in beta 2-microglobulin, MHC class I-deficient mice.

Apasov

Sitkovsky

1993

Proc. Natl. Acad. Sci. U.S.A.

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Targeted disruption of the f2-microglobulin (p2m) gene results in major histocompatibility complex (MHC) class I deficiency and virtual disappearance offunctional CD8+ cytotoxic T lymphocytes (CTLs) in 13m-deficient (132m -/-) mice. We asked whether the 32m -/-mice are able to reject Intraperitoneal (i.p.) injection of allogeneic major histocompatibility complex (MHC) class I-bearing tumor cells is followed by destruction of injected cells and survival of mice and is routinely used to obtain peritoneal exudate leukocytes (PELs) containing a,B T-cell receptor-positive (TCR+) cytotoxic T lymphocytes (CTLs) with high, MHC class I-specific lytic activity toward injected tumor cells (1-3).Cell-surface expression of MHC class I requires 12-microglobulin (32m) since no MHC class I antigens were detected on cell mutants lacking expression of 132m (4), and it is believed that 3m is needed for stabilization of peptide-H-2 complex, its correct folding, and cell membrane expression (5,6). Expression of MHC class I is considered instrumental in thymic education of MHC class I-restricted CD8+ CTLs and many studies have supported this view (7,8). It was reported that gene-targeted disruption of 2m results in the virtual disappearance of surface-expressed native MHC class I antigens and that 2m-deficient (/2m -/-) animals lack functional CD8+ CTLs (9-12). A very low percentage of or no CD8+CD4-cells were found in the thymus or periphery of (2m -/-mice with no significant effect on the development or survival of such animals, raising doubts about the functional significance of CD8+ CTLs. We confirmed in this study the original reports that naive 32m-deficient mice, in contrast to normal mice, have dramatically decreased levels of MHC class I antigen (Fig. lA a and b) and no more than 0.5% of CD8+a/3TCR+ cells were found in the thymus or peripheral organs, such as lymph nodes (Fig. lA c and d) and spleen (data not shown). We were trying to address the issue of the role of CD8+ CTLs by using an in vivo model, in which highly lytic and antigen-specific CD8+ PEL CTLs are implicated in tumor cell rejection (1-3) and could be easily recovered from peritoneal cavities of i.p. tumor-injected mice. MATERIALS AND METHODSMice. C57BL/6, 129/J (129J x C57BL/6)F1, DBA/2, and 12m -/-mice were 6-8 weeks old at the beginning of the experiments and were maintained in a pathogen-free environment. 32m -/ -mice used in the study were derived from embryonic stem cells (129/ola) in which the P2m gene was disrupted by gene targeting. Chimeras obtained from these cells were mated with C57BL/6 and offspring carrying the defective gene were crossed to obtain animals homozygous for the mutation (10).Cells. Thymocytes and lymph node cells were obtained as a single cell suspension after lymphoid organs were taken from control or immunized mice. The routine protocol was used to obtain a PEL suspension (1, 2). Briefly, (32m +/+ and/or 82m -/ -mice were i.p. injected with 6-25 x 106 P815 CTLs during immunization of P2m -/-mice) or with tumor cells gr...

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LCMV-Specific, Class II-Restricted Cytotoxic T Cells in β2-Microglobulin-Deficient Mice

Cited by 157 publications

References 30 publications

CD4+ T Cell Priming Accelerates the Clearance of Sendai Virus in Mice, but Has a Negative Effect on CD8+ T Cell Memory

CD4+ T Cell Priming Accelerates the Clearance of Sendai Virus in Mice, but Has a Negative Effect on CD8+ T Cell Memory

CD8 T Cells Inhibit Respiratory Syncytial Virus (RSV) Vaccine-Enhanced Disease

Highly lytic CD8+, alpha beta T-cell receptor cytotoxic T cells with major histocompatibility complex (MHC) class I antigen-directed cytotoxicity in beta 2-microglobulin, MHC class I-deficient mice.

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