scholarly journals Underwhelming the Immune Response: Effect of Slow Virus Growth on CD8+-T-Lymphocyte Responses

2004 ◽  
Vol 78 (5) ◽  
pp. 2247-2254 ◽  
Author(s):  
Gennady Bocharov ◽  
Burkhard Ludewig ◽  
Antonio Bertoletti ◽  
Paul Klenerman ◽  
Tobias Junt ◽  
...  
Keyword(s):  
Growth Rate ◽  
Viral Replication ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Immune Surveillance ◽  
Lymphocytic Choriomeningitis ◽  
Virus Infections ◽  
Lower Growth ◽  
Virus Growth ◽  
Ctl Responses

ABSTRACT The speed of virus replication has typically been seen as an advantage for a virus in overcoming the ability of the immune system to control its population growth. Under some circumstances, the converse may also be true: more slowly replicating viruses may evoke weaker cellular immune responses and therefore enhance their likelihood of persistence. Using the model of lymphocytic choriomeningitis virus (LCMV) infection in mice, we provide evidence that slowly replicating strains induce weaker cytotoxic-T-lymphocyte (CTL) responses than a more rapidly replicating strain. Conceptually, we show a “bell-shaped” relationship between the LCMV growth rate and the peak CTL response. Quantitative analysis of human hepatitis C virus infections suggests that a reduction in virus growth rate between patients during the incubation period is associated with a spectrum of disease outcomes, from fulminant hepatitis at the highest rate of viral replication through acute resolving to chronic persistence at the lowest rate. A mathematical model for virus-CTL population dynamics (analogous to predator [CTL]-prey [virus] interactions) is applied in the clinical data-driven analysis of acute hepatitis B virus infection. The speed of viral replication, through its stimulus of host CTL responses, represents an important factor influencing the pathogenesis and duration of virus persistence within the human host. Viruses with lower growth rates may persist in the host because they “sneak through” immune surveillance.

scholarly journals Papillomavirus Pseudovirus: a Novel Vaccine To Induce Mucosal and Systemic Cytotoxic T-Lymphocyte Responses

2001 ◽  
Vol 75 (21) ◽  
pp. 10139-10148 ◽  
Author(s):  
Wei Shi ◽  
Jianzhong Liu ◽  
Yujun Huang ◽  
Liang Qiao
Keyword(s):  
Dna Vaccine ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Oral Immunization ◽  
Lymphocytic Choriomeningitis ◽  
Lymphoid Tissues ◽  
Adjuvant Effect ◽  
Ctl Response ◽  
Lymphocyte Responses ◽  
Ctl Responses

ABSTRACT Intestinal mucosa is a portal for many infectious pathogens. Systemic immunization, in general, does not induce a cytotoxic T-lymphocyte (CTL) response at the mucosal surface. Because papillomavirus (PV) naturally infects mucosa and skin, we determined whether PV pseudovirus, i.e., PV-like particles in which unrelated DNA plasmids are packaged, could generate specific mucosal immunity. We found that the pseudovirus that encoded the lymphocytic choriomeningitis virus gp33 epitope induced a stronger CTL response than a DNA vaccine (plasmid) encoding the same epitope given systemically. The virus-like particles that were used to make the pseudoviruses provided an adjuvant effect for induction of CTLs by the DNA vaccine. The PV pseudovirus pseudoinfected mucosal and systemic lymphoid tissues when administered orally. Oral immunization with the pseudovirus encoding human PV type 16 mutant E7 induced mucosal and systemic CTL responses. In comparison, a DNA vaccine encoding E7, when given orally, did not induce a CTL response in intestinal mucosal lymphoid tissue. Further, oral immunization with the human PV pseudovirus encoding E7 protected mice against mucosal challenge with an E7-expressing bovine PV pseudovirus. Thus, PV pseudovirus can be used as a novel vaccine to induce mucosal and systemic CTL responses.

scholarly journals Bone Marrow–Derived Antigen-Presenting Cells Are Required for the Generation of Cytotoxic T Lymphocyte Responses to Viruses and Use Transporter Associated with Antigen Presentation (Tap)-Dependent and -Independent Pathways of Antigen Presentation

2000 ◽  
Vol 192 (8) ◽  
pp. 1143-1150 ◽  
Author(s):  
Luis J. Sigal ◽  
Kenneth L. Rock
Keyword(s):  
Bone Marrow ◽  
Antigen Presentation ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Antigen Presenting Cells ◽  
Lymphocytic Choriomeningitis ◽  
Ctl Response ◽  
Lymphocyte Responses ◽  
Antigen Presenting ◽  
Ctl Responses

Bone marrow (BM)-derived professional antigen-presenting cells (pAPCs) are required for the generation of cytotoxic T lymphocyte (CTL) responses to vaccinia virus and poliovirus. Furthermore, these BM-derived pAPCs require a functional transporter associated with antigen presentation (TAP). In this report we analyze the requirements for BM-derived pAPCs and TAP in the initiation of CTL responses to lymphocytic choriomeningitis virus (LCMV) and influenza virus (Flu). Our results indicate a requirement for BM-derived pAPCs for the CTL responses to these viruses. However, we found that the generation of CTLs to one LCMV epitope (LCMV nucleoprotein 396–404) was dependent on BM-derived pAPCs but, surprisingly, TAP independent. The study of the CTL response to Flu confirmed the existence of this BM-derived pAPC-dependent/TAP-independent CTL response and indicated that the TAP-independent pathway is ∼10–300-fold less efficient than the TAP-dependent pathway.

scholarly journals Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence.

1984 ◽  
Vol 160 (2) ◽  
pp. 521-540 ◽  
Author(s):  
R Ahmed ◽  
A Salmi ◽  
L D Butler ◽  
J M Chiller ◽  
M B Oldstone
Keyword(s):  
T Lymphocyte ◽  
Genetic Variants ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocytic Choriomeningitis ◽  
Lymphocytic Choriomeningitis Virus ◽  
Spleen Cells ◽  
Ctl Response ◽  
Immunocompetent Mice ◽  
Lcmv Infection ◽  
Ctl Responses

We studied the mechanism of lymphocytic choriomeningitis virus (LCMV) persistence and the suppression of cytotoxic T lymphocyte (CTL) responses in BALB/c WEHI mice infected at birth with LCMV Armstrong strain. Using adoptive transfer experiments we found that spleen cells from persistently infected (carrier) mice actively suppressed the expected LCMV-specific CTL response of spleen cells from normal adult mice. The suppression was specific for the CTL response and LCMV -specific antibody responses were not affected. Associated with the specific CTL suppression was the establishment of persistent LCMV infection. The transfer of spleen or lymph node cells containing LCMV -specific CTL resulted in virus clearance and prevented establishment of the carrier state. The suppression of LCMV -specific CTL responses by carrier spleen cells is not mediated by a suppressor cell, but is due to the presence of genetic variants of LCMV in spleens of carrier mice. Such virus variants selectively suppress LCMV-specific CTL responses and cause persistent infections in immunocompetent mice. In striking contrast, wild-type LCMV Armstrong, from which these variants were generated, induces a potent CTL response in immunocompetent mice and the LCMV infection is rapidly cleared. Our results show that LCMV variants that emerge during infection in vivo play a crucial role in the suppression of virus-specific CTL responses and in the maintenance of virus persistence.

HIV-1-Specific Cytotoxic T Lymphocyte (CTL) Responses Against Immunodominant Optimal Epitopes Slow the Progression of AIDS in China

2008 ◽  
Vol 6 (4) ◽  
pp. 335-350 ◽  
Author(s):  
Song Zhai ◽  
Yan Zhuang ◽  
Yang Song ◽  
Shu Li ◽  
Dedong Huang ◽  
...  
Keyword(s):  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hiv 1 ◽  
Ctl Responses

scholarly journals The 3′ CCACCA Sequence of tRNAAla(UGC) Is the Motif That Is Important in Inducing Th1-Like Immune Response, and This Motif Can Be Recognized by Toll-Like Receptor 3

2006 ◽  
Vol 13 (7) ◽  
pp. 733-739 ◽  
Author(s):  
Zhijun Wang ◽  
Li Xiang ◽  
Junjie Shao ◽  
Zhenghong Yuan
Keyword(s):  
Immune Responses ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Hepatitis B Surface Antigen ◽  
Toll Like Receptor ◽  
Anticodon Loop ◽  
T Helper ◽  
D Loop ◽  
Th 1 ◽  
Ctl Responses

ABSTRACT In this article, the immunogenicity of tRNA and the recognition of tRNA by Toll-like receptors (TLRs) are analyzed. Analyses of the effects of different tRNAAla(UGC) fragments (tRNAAla1-76 [corresponding to positions 1 through 76], tRNAAla26-76, tRNAAla40-76, tRNAAla62-76, tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70) on the immune responses of hepatitis B surface antigen (HBsAg) were performed with BALB/c mice. Results show that tRNAAla1-76, tRNAAla26-76, tRNAAla40-76, and tRNAAla62-76 adjuvants not only induced stronger T helper (Th) 1 immune responses but also cytotoxic-T-lymphocyte (CTL) responses relative to tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70 adjuvants in HBsAg immunization. A deletion of the D loop (tRNAAla26-76), anticodon loop (tRNAAla40-76), or TψC (tRNAAla62-76) loop of tRNAAla(UGC) does not significantly decrease the adjuvant characteristic of tRNAAla(UGC). However a deletion of the 3′-end CCACCA sequence (tRNAAla1-70, tRNAAla26-70, tRNAAla40-70, and tRNAAla62-70) of tRNAAla(UGC) significantly decreased the adjuvant characteristic in Th1 and CTL immune responses. Moreover, the recognitions of different tRNAAla(UGC) fragments by TLR3, TLR7, TLR8, and TLR9 were analyzed. Results show that a deletion of the 3′ CCACCA sequence of tRNAAla(UGC) significantly decreased the recognition by TLR3. We concluded that the 3′ CCACCA sequence of tRNAAla(UGC) is the important motif to induce Th1 and CTL responses and this motif can be effectively recognized by TLR3.

scholarly journals Sendai virus-specific, H-2-restricted cytotoxic T lymphocyte responses of nude mice grafted with allogeneic or semi-allogeneic thymus glands.

1980 ◽  
Vol 152 (6) ◽  
pp. 1805-1810 ◽  
Author(s):  
J P Lake ◽  
M E Andrew ◽  
C W Pierce ◽  
T J Braciale
Keyword(s):  
T Lymphocyte ◽  
Nude Mice ◽  
Sendai Virus ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Self Recognition ◽  
Parental Haplotype ◽  
Lymphocyte Responses ◽  
Ctl Responses

The in vitro secondary cytotoxic T lymphocyte (CTL) response to Sendai virus-treated stimulator cells by primed spleen cells from thymus gland-grafted nude mice was examined. BALB/c (H-2d) nude mice grafted with allogeneic C57BL/10 (H-2b) thymus glands developed CTL responses directed exclusively to Sendai virus-infected H-2d target cells. (C57BL/6 X BALB/c)F1 nude mice grafted with thymus glands of either parent developed CTL responses preferentially against infected target cells expressing the MHC antigens present in the parental thymus graft, but also had detectable activity for infected target cells of the parental haplotype not expressed in the thymus. These results provide evidence against the concept that self recognition by MHC-restricted CTL is directed exclusively by the MCH type of the thymus.

scholarly journals Mucosal Priming of Simian Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Responses in Rhesus Macaques by the Salmonella Type III Secretion Antigen Delivery System

2003 ◽  
Vol 77 (4) ◽  
pp. 2400-2409 ◽  
Author(s):  
David T. Evans ◽  
Li-Mei Chen ◽  
Jacqueline Gillis ◽  
Kuei-Chin Lin ◽  
Brian Harty ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Replication ◽  
T Lymphocyte ◽  
Type Iii Secretion ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
Secretion System ◽  
Type Iii ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Nearly all human immunodeficiency virus (HIV) infections are acquired mucosally, and the gut-associated lymphoid tissues are important sites for early virus replication. Thus, vaccine strategies designed to prime virus-specific cytotoxic T lymphocyte (CTL) responses that home to mucosal compartments may be particularly effective at preventing or containing HIV infection. The Salmonella type III secretion system has been shown to be an effective approach for stimulating mucosal CTL responses in mice. We therefore tested ΔphoP-phoQ attenuated strains of Salmonella enterica serovar Typhimurium and S. enterica serovar Typhi expressing fragments of the simian immunodeficiency virus (SIV) Gag protein fused to the type III-secreted SopE protein for the ability to prime virus-specific CTL responses in rhesus macaques. Mamu-A*01 + macaques were inoculated with three oral doses of recombinant Salmonella, followed by a peripheral boost with modified vaccinia virus Ankara expressing SIV Gag (MVA Gag). Transient low-level CTL responses to the Mamu-A*01 Gag181-189 epitope were detected following each dose of Salmonella. After boosting with MVA Gag, strong Gag-specific CTL responses were consistently detected, and tetramer staining revealed the expansion of Gag181-189-specific CD8+ T-cell responses in peripheral blood. A significant percentage of the Gag181-189-specific T-cell population in each animal also expressed the intestinal homing receptor α4β7. Additionally, Gag181-189-specific CD8+ T cells were detected in lymphocytes isolated from the colon. Yet, despite these responses, Salmonella-primed/MVA-boosted animals did not exhibit improved control of virus replication following a rectal challenge with SIVmac239. Nevertheless, this study demonstrates the potential of mucosal priming by the Salmonella type III secretion system to direct SIV-specific cellular immune responses to the gastrointestinal mucosa in a primate model.

Residual Lymphocytes in GM-CSF and IL-15 Differentiated Monocyte-Derived Dendritic Cells Enables Cytotoxic T Lymphocyte Responses.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4907-4907
Author(s):  
Melinda Y. Hardy ◽  
Andrew J. Kassianos ◽  
Ray Wilkinson ◽  
Annelie Vulink ◽  
Derek N.J. Hart ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Small Population ◽  
Lymphoid Cells ◽  
Gm Csf ◽  
Hla Dr ◽  
Ifn Γ ◽  
Human Dendritic Cells ◽  
Ctl Responses

Abstract We investigated the capacity of IL-15 to differentiate human dendritic cells (DC) from monocytes in the presence of GM-CSF (IL-15 MoDC) and compared them with MoDC differentiated in IL-4 and GM-CSF (IL-4 MoDC) as used in many immunotherapy protocols. IL-15 MoDC expressed higher levels of CD40 and HLA-DR and importantly, induced MART-1 specific cytotoxic T lymphocyte (CTL) responses with superior lytic capacity, when compared to IL-4 MoDC. In response to activation, IL-15 MoDC secreted high levels of IFN-γbut low or no IL-12, whereas IL-4 MoDC secreted high IL-12 but low or no IFN-γ. Using an IFN-γ blocking antibody, we demonstrated that IFN-γ production by the IL-15 MoDC did not account for the superior CTL responses induced. Despite immunoselecting monocytes to greater than 97% purity prior to DC differentiation, we noticed a small population (1–2%) of CD56+ and CD3+ lymphocytes in the IL-15 MoDC preparations that were less prominent in IL-4 MoDC differentiated from the same monocytes. Removal of the residual lymphocytes from monocytes prior to differentiation into IL-15 MoDC diminished their capacity to induce CTL but did not affect the expression of HLA-DR or CD40. These data suggest that IL-15-dependent cross-talk between the small lymphoid populations present and DC, during DC differentiation from monocytes results in superior CTL priming that is independent of IL-12 and IFN-γ. Based on these results, appropriately manufactured IL-15 MoDC preparations containing defined numbers of lymphoid cells should be considered for immunotherapy.

scholarly journals B7 Costimulation Is Critical for Antibody Class Switching and CD8+ Cytotoxic T-Lymphocyte Generation in the Host Response to Vesicular Stomatitis Virus

2000 ◽  
Vol 74 (1) ◽  
pp. 203-208 ◽  
Author(s):  
Alexander J. McAdam ◽  
Evan A. Farkash ◽  
Benjamin E. Gewurz ◽  
Arlene H. Sharpe
Keyword(s):  
Viral Infection ◽  
Vesicular Stomatitis Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Specific Class ◽  
Wild Type ◽  
B7 Molecules ◽  
Vesicular Stomatitis ◽  
Ctl Responses

ABSTRACT Antibody and cytotoxic T-lymphocyte (CTL) responses have critical roles in eliminating many viral infections. In addition to stimulation of the T-cell receptor, T cells require costimulatory signals to respond optimally. We evaluated the role of B7 costimulatory molecules (B7-1 and B7-2) in the immune response to viral infection using vesicular stomatitis virus (VSV) and mice lacking either B7-1 or B7-2 or both molecules. Mice lacking both B7-1 and B7-2 had essentially no anti-VSV immunoglobulin G1 (IgG1) response, decreased IgG2a responses, and normal IgM responses, while mice lacking either B7-1 or B7-2 had unaltered anti-VSV antibody responses compared to wild-type mice. Depletion of CD4+ cells further reduced the IgG2a response in mice lacking both B7 molecules, suggesting that CD4−cells may supply help for IgG2a in the absence of B7 costimulation. The absence of both B7 molecules profoundly reduced generation of both primary and secondary VSV-specific class I major histocompatibility complex (MHC)-restricted CTL, whereas VSV-specific CTL responses in mice lacking either B7-1 or B7-2 were similar to those of wild-type animals. Class I MHC-restricted CTL in wild-type mice were not dependent on CD4+ cells, suggesting that the failure of CTL in the absence of B7s is due to a lack of B7 costimulation directly to the CD8+ CTL. These data demonstrate that B7-1 and B7-2 have critical, overlapping functions in the antibody and CTL responses to this viral infection.

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