scholarly journals Thymic selection and adaptability of cytotoxic T lymphocyte responses in transgenic mice expressing a viral protein in the thymus.

1994 ◽  
Vol 180 (5) ◽  
pp. 1901-1910 ◽  
Author(s):  
M G von Herrath ◽  
J Dockter ◽  
M Nerenberg ◽  
J E Gairin ◽  
M B Oldstone
Keyword(s):  
T Lymphocytes ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Lymphocytic Choriomeningitis ◽  
Target Cells ◽  
Viral Glycoprotein ◽  
Specific Lysis ◽  
Ctl Response ◽  
Selection Processes ◽  
Np Gene

Upon primary challenge with lymphocytic choriomeningitis virus (LCMV), H-2d (BALB/cByJ) mice mount a cytotoxic T lymphocyte (CTL) response to a single immunodominant domain of the viral nucleoprotein (NP) but no detectable response to the viral glycoprotein (GP). To manipulate this CTL response, the viral NP gene was expressed in the thymus and peripheral T lymphocytes using the murine Thy1.2 promoter. As a result, such Thy1.2-NP (H-2d) transgenic (tg) mice deleted their high-affinity anti-LCMV-NP CTL, but generated equal numbers of lower-affinity NP CTL. Further, they made an alternative anti-LCMV-GP CTL response that is not normally found in non-tg mice indicating a hierarchial control of the CTL response. Unlike the H-2d mice, H-2b (C57Bl/6J) mice normally mount a CTL response to both LCMV-GP and -NP. When the LCMV-NP was expressed using the Thy1.2 promoter in these H-2b mice, the LCMV-NP-specific CTL response was completely aborted and no CTL to new, alternative viral epitopes were generated. Dilutions of H-2b or H-2d NP peptides indicated that 3-4 logs less H-2b NP peptide was required to sensitize syngeneic target cells for CTL-specific lysis, suggesting that the differing affinities of H-2b and H-2d major histocompatibility complex molecules for their peptides likely account for the total removal of NP CTL in the H-2b mice but only partial removal in H-2d mice made to express thymic NP. Thymic grafting experiments done with thymi from newborn Thy1.2-NP tg mice show that selection processes studied in this model are of central (thymic) origin and are not caused by Thy1.2-positive LCMV-NP-expressing T lymphocytes in the periphery.

scholarly journals Human HLA-A0201-restricted cytotoxic T lymphocyte recognition of influenza A is dominated by T cells bearing the V beta 17 gene segment.

1995 ◽  
Vol 181 (1) ◽  
pp. 79-91 ◽  
Author(s):  
P J Lehner ◽  
E C Wang ◽  
P A Moss ◽  
S Williams ◽  
K Platt ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Influenza A ◽  
Cytotoxic T Lymphocyte ◽  
Gene Segment ◽  
Cell Subpopulation ◽  
Specific Lysis ◽  
Ctl Response ◽  
The Matrix ◽  
Limiting Dilution

The major histocompatibility complex class I-restricted cytotoxic T lymphocyte (CTL) response is important in the clearance of viral infections in humans. After influenza A infection, a peptide from the matrix protein, M58-66, is presented in the context of the MHC allele HLA-A0201 and the resulting CTL response is detectable in most HLA-A0201 subjects. An initial study suggested that M58-66-specific CTL clones show conserved T cell receptor (TCR) alpha and beta gene segments. We have addressed the significance of this observation by determining the expression of V beta 17 during the development of M58-66-specific CTL lines in 21 unrelated HLA-A0201 subjects, and analyzing TCR usage by M58-66-specific CTL clones. TCR V beta 17 was the dominant V beta segment used and CD8 V beta 17 expansion correlated with M58-66-specific lysis. Limiting dilution analysis from five subjects showed the M58-66 CTL precursor frequency to vary between 1/54,000 and less than 1/250,000, and that up to 85% of the matrix peptide (M58-66)-specific CTL used the V beta 17 gene segment. The M58-66 specific CTL response was dependent on previous viral exposure and specific V beta 17 expansion, as it was not found in cord blood, despite a readily expandable V beta 17+ CD8+ T cell subpopulation. Sequence analysis of 38 M58-66-specific V beta 17 transcripts from 13 subjects revealed extensive conservation in the CDR3 region including conservation of an arginine-serine motif. To test the dependence of this CTL response on the V beta 17 gene segment, peripheral blood lymphocytes were depleted of CD8+ TCR V beta 17+ cells, before the generation of M58-66-specific CTL. In most cases such depletion blocked or severely reduced the generation of the M58-66-specific response, and under limiting dilution conditions could abolish M58-66-specific CTL precursors. These studies reveal the dependence of this natural human immune response on a particular TCR gene segment.

scholarly journals H-2Db−/− Mice Are Susceptible to Persistent Infection by Theiler's Virus

2000 ◽  
Vol 74 (12) ◽  
pp. 5470-5476 ◽  
Author(s):  
Arièle Azoulay-Cayla ◽  
Sven Dethlefs ◽  
Béatrice Pérarnau ◽  
Eva-Lotta Larsson-Sciard ◽  
François A. Lemonnier ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
T Lymphocyte ◽  
Persistent Infection ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
Theiler's Virus ◽  
Ctl Response ◽  
The Central Nervous System

ABSTRACT H-2b mice are resistant to persistent infection of the central nervous system by Theiler's virus. They clear the infection 7 to 10 days after intracranial inoculation. Resistance maps to the H-2D gene and not to the H-2K gene and is associated with a potent antiviral cytotoxic T-lymphocyte (CTL) response. We used H-2b mice in which theH-2D or the H-2K gene had been inactivated to dissect the respective roles of these genes in resistance. We report that H-2D −/− but notH-2K −/− mice were susceptible to persistent infection. Furthermore, whereas H-2K −/−mice mounted a vigorous virus-specific CTL response, similar to that of control C57BL/6 mice, the CTL response ofH-2D −/− mice was nil or minimal. Using target cells transfected with the H-2Db or theH-2Kb gene, we showed that theH-2K-restricted CTL response against the virus was minimal in H-2D −/− mice. These results demonstrate that the H-2Db andH-2Kb genes play nonredundant roles in the resistance to this persistent infection.

scholarly journals Common Antiviral Cytotoxic T-Lymphocyte Epitope for Diverse Arenaviruses

2001 ◽  
Vol 75 (14) ◽  
pp. 6273-6278 ◽  
Author(s):  
Michael B. A. Oldstone ◽  
Hanna Lewicki ◽  
Dirk Homann ◽  
Christophe Nguyen ◽  
Sylvianne Julien ◽  
...  
Keyword(s):  
Amino Acids ◽  
T Lymphocyte ◽  
New World ◽  
Cytotoxic T Lymphocyte ◽  
Lassa Fever ◽  
Lymphocytic Choriomeningitis ◽  
Target Cells ◽  
Old World ◽  
Ctl Epitope ◽  
Lassa Fever Virus

ABSTRACT Members of the Arenaviridae family have been isolated from mammalian hosts in disparate geographic locations, leading to their grouping as Old World types (i.e., lymphocytic choriomeningitis virus [LCMV], Lassa fever virus [LFV], Mopeia virus, and Mobala virus) and New World types (i.e., Junin, Machupo, Tacaribe, and Sabia viruses) (C. J. Peters, M. J. Buchmeier, P. E. Rollin, and T. G. Ksiazek, p. 1521–1551, in B. N. Fields, D. M. Knipe, and P. M. Howley [ed.], Fields virology, 3rd ed., 1996; P. J. Southern, p. 1505–1519, in B. N. Fields, D. M. Knipe, and P. M. Howley [ed.], Fields virology, 3rd ed., 1996). Several types in both groups—LFV, Junin, Machupo, and Sabia viruses—cause severe and often lethal human diseases. By sequence comparison, we noted that eight Old World and New World arenaviruses share several amino acids with the nucleoprotein (NP) that consists of amino acids (aa) 118 to 126 (NP 118–126) (RPQASGVYM) of LCMV that comprise the immunodominant cytotoxic T-lymphocyte (CTL) epitope forH-2 d mice (32). This Ld-restricted epitope constituted >97% of the total bulk CTLs produced in the specific antiviral or clonal responses ofH-2 d BALB mice. NP 118–126 of the Old World arenaviruses LFV, Mopeia virus, and LCMV and the New World arenavirus Sabia virus bound at high affinity to Ld. The primary H-2 d CTL anti-LCMV response as well as that of a CTL clone responsive to LCMV NP 118–126 recognized target cells coated with NP 118–126 peptides derived from LCMV, LFV, and Mopeia virus but not Sabia virus, indicating that a common functional NP epitope exists among Old World arenaviruses. Use of site-specific amino acid exchanges in the NP CTL epitope among these arenaviruses identified amino acids involved in major histocompatibility complex binding and CTL recognition.

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 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 Resistance of cytotoxic T lymphocytes to the lytic effects of their toxic granules.

1987 ◽  
Vol 166 (5) ◽  
pp. 1536-1547 ◽  
Author(s):  
C R Verret ◽  
A A Firmenich ◽  
D M Kranz ◽  
H N Eisen
Keyword(s):  
T Cells ◽  
T Lymphocytes ◽  
Cell Lines ◽  
Cytotoxic T Lymphocytes ◽  
T Lymphocyte ◽  
Target Cell ◽  
Cytotoxic T Lymphocyte ◽  
The Other ◽  
Target Cells ◽  
Resistant Cells

A cytotoxic T lymphocyte (CTL) characteristically kills target cells one after the other by releasing toxic granules that contain one or more cytolytic components. To determine how CTLs avoid destroying themselves when they release granules and lyse target cells, 7 murine CD8+ CTL cell lines were compared with 19 other cell lines for susceptibility to lysis by the isolated toxic granules. Murine CD8+ CTLs were clearly the most resistant cells: granules did not lyse them even after they were exposed to azide, cyanide, and 2-deoxyglucose, conditions that were found to enhance the susceptibility of all the other cells tested, including other T cells. Thus, resistance of CD8+ CTLs to cytotoxic granules appears to be independent of cellular ATP. To reconcile these findings with other observations that, under some circumstances, CTLs can be lysed by other CTLs, we suggest a model in which a CTL releases only a limited proportion of its toxic granules at each antigen-specific encounter with a target cell; the amount released is sufficient to kill most target cells but to leave the CTL undamaged and with enough granules to attack other target cells.

scholarly journals Monoclonal anti-Lyt-2.2 antibody blocks lectin-dependent cellular cytotoxicity of H-2-negative target cells.

1984 ◽  
Vol 159 (2) ◽  
pp. 551-558 ◽  
Author(s):  
T Hünig
Keyword(s):  
Monoclonal Antibody ◽  
T Lymphocyte ◽  
Target Cell ◽  
Cytotoxic T Lymphocyte ◽  
Cell Interaction ◽  
Target Cells ◽  
Cellular Cytotoxicity ◽  
Specific Lysis ◽  
Bearing Structure ◽  
Negative Target

The hypothesis that blocking of cytotoxic T lymphocyte (CTL)-mediated cytolysis with anti-Lyt-2 antibodies acts at the level of inhibiting the interaction of the Lyt-2-bearing structure with H-2 class I molecules was tested. In agreement with the findings of others, purified anti-Lyt-2.2 inhibited both antigen-specific lysis and lectin-dependent cellular cytotoxicity (LDCC). LDCC of H-2-positive and H-2-negative target cells was similarly inhibited by this antibody. As expected, this effect was specific for CTL expressing the Lyt-2.2 allele, in contrast to blocking with a rat monoclonal antibody to the murine LFA-1 antigen. The implications of this finding for the function of the Lyt-2 antigen in CTL-target cell interaction are discussed.

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.

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