scholarly journals Expression of Interleukin-4 by Recombinant Respiratory Syncytial Virus Is Associated with Accelerated Inflammation and a Nonfunctional Cytotoxic T-Lymphocyte Response following Primary Infection but Not following Challenge with Wild-Type Virus

2005 ◽  
Vol 79 (15) ◽  
pp. 9515-9526 ◽  
Author(s):  
Alexander Bukreyev ◽  
Igor M. Belyakov ◽  
Gregory A. Prince ◽  
Kevin C. Yim ◽  
Katie K. Harris ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Respiratory Syncytial Virus ◽  
Inflammatory Response ◽  
T Lymphocyte ◽  
Primary Infection ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 4 ◽  
Wild Type ◽  
Ctl Response ◽  
Syncytial Virus

ABSTRACT The outcome of a viral infection or of immunization with a vaccine can be influenced by the local cytokine environment. In studies of experimental vaccines against respiratory syncytial virus (RSV), an increased stimulation of Th2 (T helper 2) lymphocytes was associated with increased immunopathology upon subsequent RSV infection. For this study, we investigated the effect of increased local expression of the Th2 cytokine interleukin-4 (IL-4) from the genome of a recombinant RSV following primary infection and after a challenge with wild-type (wt) RSV. Mice infected with RSV/IL-4 exhibited an accelerated pulmonary inflammatory response compared to those infected with wt RSV, although the wt RSV group caught up by day 8. In the first few days postinfection, RSV/IL-4 was associated with a small but significant acceleration in the expansion of pulmonary T lymphocytes specific for an RSV CD8+ cytotoxic T-lymphocyte (CTL) epitope presented as a major histocompatibility complex class I tetramer. However, by day 7 the response of tetramer-positive T lymphocytes in the wt RSV group caught up and exceeded that of the RSV/IL-4 group. At all times, the CTL response of the RSV/IL-4 group was deficient in the production of gamma interferon and was nonfunctional for in vitro cell killing. The accelerated inflammatory response coincided with an accelerated accumulation and activation of pulmonary dendritic cells early in infection, but thereafter the dendritic cells were deficient in the expression of B7-1, which governs the acquisition of cytolytic activity by CTL. Following a challenge with wt RSV, there was an increase in Th2 cytokines in the animals that had previously been infected with RSV/IL-4 compared to those previously infected with wt RSV, but the CD8+ CTL response and the amount of pulmonary inflammation were not significantly different. Thus, a strong Th2 environment during primary pulmonary immunization with live RSV resulted in early inflammation and a largely nonfunctional primary CTL response but had a minimal effect on the secondary response.

scholarly journals The Cysteine-Rich Region and Secreted Form of the Attachment G Glycoprotein of Respiratory Syncytial Virus Enhance the Cytotoxic T-Lymphocyte Response despite Lacking Major Histocompatibility Complex Class I-Restricted Epitopes

2006 ◽  
Vol 80 (12) ◽  
pp. 5854-5861 ◽  
Author(s):  
Alexander Bukreyev ◽  
Maria Elina Serra ◽  
Federico R. Laham ◽  
Guillermina A. Melendi ◽  
Steven R. Kleeberger ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Respiratory Syncytial Virus ◽  
Major Histocompatibility Complex Class ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Complex Class ◽  
Rich Region ◽  
Ctl Response ◽  
Histocompatibility Complex ◽  
Syncytial Virus

ABSTRACT The cytotoxic T-lymphocyte (CTL) response is important for the control of viral replication during respiratory syncytial virus (RSV) infection. The attachment glycoprotein (G) of RSV does not encode major histocompatibility complex class I-restricted epitopes in BALB/c mice (H-2 d ). Furthermore, studies to date have described an absence of significant CTL activity directed against this protein in humans. Therefore, G previously was not considered necessary for the generation of RSV-specific CTL responses. In this study, we demonstrate that, despite lacking H-2d-restricted epitopes, G enhances the generation of an effective CTL response against RSV. Furthermore, we show that this stimulatory effect is independent of virus titers and RSV-induced inflammation; that it is associated primarily with the secreted form of G; and that the effect depends on the cysteine-rich region of G (GCRR), a segment conserved in wild-type isolates worldwide. These findings reveal a novel function for the GCRR with potential implications for the generation of protective cellular responses and vaccine development.

scholarly journals Interleukin-4 Diminishes CD8+ Respiratory Syncytial Virus-Specific Cytotoxic T-Lymphocyte Activity In Vivo

1999 ◽  
Vol 73 (11) ◽  
pp. 8944-8949 ◽  
Author(s):  
Sandra Aung ◽  
Yi-Wei Tang ◽  
Barney S. Graham
Keyword(s):  
Respiratory Syncytial Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Recombinant Vaccinia Virus ◽  
Cytolytic Activity ◽  
Interleukin 4 ◽  
Ifn Γ ◽  
Syncytial Virus ◽  
Ctl Activity

ABSTRACT Although interleukin-4 (IL-4) has been implicated in respiratory syncytial virus (RSV)-enhanced disease, the mechanism by which it modulates immune responses to primary RSV infection remains unclear. We have developed a system to investigate the effect of IL-4 on RSV epitope-specific cytotoxic T-lymphocyte (CTL) effector function in vivo, using an H-2Kd -restricted RSV M2 epitope. BALB/c mice were infected with recombinant vaccinia virus (rVV) constructed to express RSV M2 protein (vvM2) alone or coexpress M2 and IL-4 (vvM2/IL-4). Splenocytes were assessed for M2-specific CTL activity in a direct 51Cr release assay and intracellular gamma interferon (IFN-γ) production by fluorescence-activated cell sorting analysis. Mice infected with vvM2/IL-4 had less M2-specific primary CTL activity than those infected with vvM2. M2-specific CTL frequency, as measured by M2 peptide-induced intracellular IFN-γ production, was diminished in the vvM2/IL-4 group, partially accounting for the reduction of CTL activity. Mice immunized with either construct were challenged intravenously with RSV 4 weeks postimmunization, and direct CTL were measured. These results demonstrate that local expression of IL-4, at the time of antigen presentation, diminishes the cytolytic activity of primary and memory CD8+ RSV-specific CTL responses in vivo.

scholarly journals Shifting immunodominance pattern of two cytotoxic T-lymphocyte epitopes in the F glycoprotein of the Long strain of respiratory syncytial virus

2004 ◽  
Vol 85 (11) ◽  
pp. 3229-3238 ◽  
Author(s):  
Carolina Johnstone ◽  
Patricia de León ◽  
Francisco Medina ◽  
José A. Melero ◽  
Blanca García-Barreno ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Vaccinia Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Recombinant Vaccinia Virus ◽  
Recombinant Vaccinia ◽  
F Protein ◽  
Syncytial Virus ◽  
Lymphocyte Responses

Human respiratory syncytial virus (RSV) is a major cause of respiratory infection in children and in the elderly. The RSV fusion (F) glycoprotein has long been recognized as a vaccine candidate as it elicits cytotoxic T-lymphocyte (CTL) and antibody responses. Two murine H-2Kd-restricted CTL epitopes (F85–93 and F92–106) are known in the F protein of the A2 strain of RSV. F-specific CTL lines using BCH4 fibroblasts that are persistently infected with the Long strain of human RSV as stimulators were generated, and it was found that in this strain only the F85–93 epitope is conserved. Motif based epitope prediction programs and an F2 chain deleted F protein encoded in a recombinant vaccinia virus enabled identification of a new epitope in the Long strain, F249–258, which is presented by Kd as a 9-mer (TYMLTNSEL) or a 10-mer (TYMLTNSELL) peptide. The results suggest that the 10-mer might be a naturally processed endogenous Kd ligand. The CD8+ T-lymphocyte responses to epitopes F85–93 and F249–258 present in the F protein of RSV Long were found to be strongly skewed to F85–93 in in vitro multispecific CTL lines and in vivo during a secondary response to a recombinant vaccinia virus that expresses the entire F protein. However, no hierarchy in CD8+ T-lymphocyte responses to F85–93 and F249–258 epitopes was observed in vivo during a primary response.

scholarly journals Soluble proteins delivered to dendritic cells via pH-sensitive liposomes induce primary cytotoxic T lymphocyte responses in vitro.

1992 ◽  
Vol 175 (2) ◽  
pp. 609-612 ◽  
Author(s):  
S Nair ◽  
F Zhou ◽  
R Reddy ◽  
L Huang ◽  
B T Rouse
Keyword(s):  
Dendritic Cells ◽  
T Lymphocyte ◽  
Antigen Processing ◽  
Vaccine Development ◽  
Cytotoxic T Lymphocyte ◽  
Present Report ◽  
Soluble Proteins ◽  
Ph Sensitive ◽  
Ctl Response

Effective immunity to many infectious agents, particularly viruses, requires a CD8+ cytotoxic T lymphocyte (CTL) response. Understanding how to achieve CTL induction with soluble proteins is important for vaccine development since such antigens are usually not processed appropriately to induce CTL. In the present report, we have demonstrated that a potent primary CTL response against a soluble protein can be achieved by delivering antigen in pH-sensitive liposomes to dendritic cells (DC) either in vivo or in vitro. Since the pH-sensitive liposome delivery system is efficient and easy to use, the approach promises to be valuable both in the study of basic mechanisms in antigen processing, and as a practical means of immunization.

scholarly journals Infection of lymphocytes by a virus that aborts cytotoxic T lymphocyte activity and establishes persistent infection.

1991 ◽  
Vol 174 (1) ◽  
pp. 203-212 ◽  
Author(s):  
P Borrow ◽  
A Tishon ◽  
M B Oldstone
Keyword(s):  
Immune System ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Persistent Infection ◽  
Infectious Virus ◽  
Cytotoxic T Lymphocyte ◽  
Lymphoid Tissues ◽  
Wild Type ◽  
Ctl Response ◽  
Adult Mice

For viruses to establish persistent infections in their hosts, they must possess some mechanism for evading clearance by the immune system. When inoculated into adult immunocompetent mice, wild-type lymphocytic choriomeningitis virus (LCMV ARM) induces a CD8(+)-mediated cytotoxic T lymphocyte (CTL) response that clears the infection within 7-14 d (CTL+ [P-]). By contrast, variant viruses isolated from lymphoid tissues of persistently infected mice fail to induce a CTL response and are thus able to establish a persistent infection in adult mice (CTL- [P+]). This report compares the interaction of CTL+ (P-) and CTL- (P+) viruses with cells of the immune system. Both types of virus initially bind to 2-4% of CD4+ and CD8+ T lymphocytes and replicate within cells of both subsets. The replication of CTL- (P+) and CTL+ (P-) viruses in lymphocytes in vivo is similar for the first 5 d after initiating infection. Thereafter, in mice infected with CTL- (P+) variants, lymphocytes retain viral genetic information, and infectious virus can be recovered throughout the animals' lives. In contrast, when adult mice are infected with wild-type CTL+ (P-) LCMV ARM, virus is not recovered from lymphocytes for greater than 7 d after infection. A CD8(+)-mediated anti-LCMV CTL response is induced in such mice. Clearance of infected lymphocytes is produced by these LCMV-specific CTLs, as shown by their ability to lyse lymphocytes expressing LCMV determinants in vitro and the fact that depletion of CD8+ lymphocytes before infection with CTL+ (P-) viruses results in levels of infected lymphocytes similar to those found in undepleted CTL- (P+)-infected mice. Hence, CTL-mediated lysis of T lymphocytes carrying infectious virus is a critical factor determining whether virus persists or the infection is terminated.

scholarly journals Prophylactic Treatment with a G Glycoprotein Monoclonal Antibody Reduces Pulmonary Inflammation in Respiratory Syncytial Virus (RSV)-Challenged Naïve and Formalin-Inactivated RSV-Immunized BALB/c Mice

2010 ◽  
Vol 84 (18) ◽  
pp. 9632-9636 ◽  
Author(s):  
Gertrud U. Radu ◽  
Hayat Caidi ◽  
Congrong Miao ◽  
Ralph A. Tripp ◽  
Larry J. Anderson ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Respiratory Syncytial Virus ◽  
Inflammatory Response ◽  
G Protein ◽  
Primary Infection ◽  
Prophylactic Treatment ◽  
Pulmonary Inflammation ◽  
Rsv Infection ◽  
Pulmonary Inflammatory Response ◽  
Syncytial Virus

ABSTRACT We examined whether prophylactically administered anti-respiratory syncytial virus (anti-RSV) G monoclonal antibody (MAb) would decrease the pulmonary inflammation associated with primary RSV infection and formalin-inactivated RSV (FI-RSV)-enhanced disease in mice. MAb 131-2G administration 1 day prior to primary infection reduced the pulmonary inflammatory response and the level of RSV replication. Further, intact or F(ab′)2 forms of MAb 131-2G administered 1 day prior to infection in FI-RSV-vaccinated mice reduced enhanced inflammation and disease. This study shows that an anti-RSV G protein MAb might provide prophylaxis against both primary infection and FI-RSV-associated enhanced disease. It is possible that antibodies with similar reactivities might prevent enhanced disease and improve the safety of nonlive virus vaccines.

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