Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

Dix, Richard D.; Podack, Eckhard R.; Cousins, Scott W.

doi:10.1128/jvi.77.6.3402-3408.2003

Cited by 31 publications

(27 citation statements)

References 44 publications

(53 reference statements)

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“…However, we observed no difference in FasL −/− deficient mice, suggesting the inhibitory mechanism is independent of this pathway. It may be that other killing mechanisms or cell types are involved (47), for example, Treg cells, which use granzyme B to resolve inflammation after RSV infection (48), or CD8 cells, which have been shown to kill lymphocytic choriomeningitis virus-infected B cells (49). CD8 T cells have been shown to downregulate the Th2 CD4 T-cell response to RSV (50), and transferring RSV-specific CD8 cells into adult mice has an inhibitory effect on antibody responses (51).…”

Section: Discussionmentioning

confidence: 99%

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

Tregoning

Wang

McDonald

et al. 2013

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

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Respiratory syncytial virus (RSV) infects most children in the first year of life and is a major single cause of hospitalization in infants and young children. There is no effective vaccine, and antibody generated by primary neonatal infection is poorly protective against reinfection even with antigenically homologous viral strains. Studying the immunological basis of these observations in neonatal mice, we found that antibody responses to infection were low and unaffected by CD4 depletion, in contrast with adult mice, which had stronger CD4-dependent antibody responses. Natural killer cell depletion or codepletion of CD4 + and CD8 + cells during neonatal RSV infection caused a striking increase in anti-RSV antibody titer. These cells are major sources of the cytokine IFN-γ, and blocking IFN-γ also enhanced RSV-specific antibody responses in neonates. In addition, infection with a recombinant RSV engineered to produce IFN-γ reduced antibody titer, confirming that IFN-γ plays a pivotal role in inhibition of antibody responses after neonatal infection. These unexpected findings show that the induction of a strong cellular immune response may limit antibody responses in early life and that vaccines that induce IFN-γ-secreting cells might, in some situations, be less protective than those that do not.viral infection | bronchiolitis | lung infection

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Section: Discussionmentioning

confidence: 99%

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

Tregoning

Wang

McDonald

et al. 2013

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

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“…The primer sequences, annealing temperature, and the number of cycles for IL-2, IFN-γ, CD40L, GAPDH, FasL, PFP, and CVB3 genomes were as published elsewhere [6,[22][23][24][25]. The PCR was performed denaturation at 94°C for 1 min, primer annealing for 2 min, and primer extension at 72°C for 3 min.…”

Section: Amplification Of Cdna By Pcrmentioning

confidence: 99%

Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3

Seko¹,

Yagita²,

Okumura³

et al. 2007

Cardiovascular Research

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Objective: This study was designed to investigate the roles of programmed death-1 (PD-1) and PD-1ligands (PD-L) in the development of murine acute myocarditis caused by Coxsackievirus B3. PD-1/PD-L belong to the CD28/B7 superfamily, and the PD-1/PD-L pathway is known to transduce a negative immunoregulatory signal that antagonizes the T-cell receptor-CD28 signal and inhibits T-cell activation. Methods: We first analyzed the expression of PD-L1/PD-L2 on cardiac myocytes in vivo and in vitro. Second, we examined the effects of in vivo treatment with an anti-PD-1, PD-L1, or PD-L2 monoclonal antibodies on the development of myocardial inflammation in C3H/He mice infected with Coxsackievirus B3. Third, to investigate the effects of anti-PD-1 monoclonal antibody treatment on the activation of the infiltrating cells, we examined the expression of interleukin (IL)-2, interferon (IFN)-γ, CD40 ligand (CD40L), Fas ligand (FasL), and perforin as activation markers in mouse hearts by a semiquantitative PCR method. Results: PD-L1 was markedly induced on cardiac myocytes with acute myocarditis. In vivo anti-PD-1 or -PD-L1 blocking monoclonal antibody treatment increased the myocardial inflammation whereas anti-PD-1 stimulating monoclonal antibody treatment decreased the myocardial inflammation, and anti-PD-L2 monoclonal antibody treatment had no effect. Anti-PD-1 monoclonal antibody treatment significantly increased the expression of IFN-γ, FasL, CD40L, perforin, and Coxsackievirus B3 genomes in myocardial tissue. Conclusion: Our findings strongly suggest that the PD-1/PD-L1 pathway played a pivotal role in suppressing myocardial inflammation and raise the possibility of immunotherapy by stimulating the PD-1/PD-L1 pathway to prevent myocardial damage in viral myocarditis.

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“…NK cells mediate resistance to viruses in at least three different ways. These include direct recognition and lysis of virus-infected cells (1)(2)(3)(4), production of antiviral cytokines such as IFN-g (5)(6)(7)(8), and modulation of the adaptive antiviral immune response (9)(10)(11)(12)(13). NK cell deficiency and functional abnormalities in humans correlate with an increased susceptibility to virus infections (14)(15)(16).…”

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confidence: 99%

Expansion and Protection by a Virus-Specific NK Cell Subset Lacking Expression of the Inhibitory NKR-P1B Receptor during Murine Cytomegalovirus Infection

Rahim

Wight

Mahmoud

et al. 2016

The Journal of Immunology

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NK cells play a major role in immune defense against human and murine CMV (MCMV) infection. Although the MCMV genome encodes for MHC class I–homologous decoy ligands for inhibitory NK cell receptors to evade detection, some mouse strains have evolved activating receptors, such as Ly49H, to recognize these ligands and initiate an immune response. In this study, we demonstrate that approximately half of the Ly49H-expressing (Ly49H+) NK cells in the spleen and liver of C57BL/6 mice also express the inhibitory NKR-P1B receptor. During MCMV infection, the NKR-P1B−Ly49H+ NK cell subset proliferates to constitute the bulk of the NK cell population. This NK cell subset also confers better protection against MCMV infection compared with the NKR-P1B+Ly49H+ subset. The two populations are composed of cells that differ in their surface expression of receptors such as Ly49C/I and NKG2A/C/E, as well as developmental markers, CD27 and CD11b, and the high-affinity IL-2R (CD25) following infection. Although the NKR-P1B+ NK cells can produce effector molecules such as IFNs and granzymes, their proliferation is inhibited during infection. A similar phenotype in MCMV-infected Clr-b–deficient mice, which lack the ligand for NKR-P1B, suggests the involvement of ligands other than the host Clr-b. Most interestingly, genetic deficiency of the NKR-P1B, but not Clr-b, results in accelerated virus clearance and recovery from MCMV infection. This study is particularly significant because the mouse NKR-P1B:Clr-b receptor:ligand system represents the closest homolog of the human NKR-P1A:LLT1 system and may have a direct relevance to human CMV infection.

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Loss of the Perforin Cytotoxic Pathway Predisposes Mice to Experimental Cytomegalovirus Retinitis

Cited by 31 publications

References 44 publications

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

Roles of programmed death-1 (PD-1)/PD-1 ligands pathway in the development of murine acute myocarditis caused by coxsackievirus B3

Expansion and Protection by a Virus-Specific NK Cell Subset Lacking Expression of the Inhibitory NKR-P1B Receptor during Murine Cytomegalovirus Infection

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