scholarly journals Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex.

1991 ◽  
Vol 173 (4) ◽  
pp. 1007-1015 ◽  
Author(s):  
A Vitiello ◽  
D Marchesini ◽  
J Furze ◽  
L A Sherman ◽  
R W Chesnut
Keyword(s):  
Transgenic Mice ◽  
T Lymphocyte ◽  
Matrix Protein ◽  
Cytotoxic T Lymphocyte ◽  
Dominant Role ◽  
Class I ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Restriction Element ◽  
Hla A2.1

Transgenic murine lines have been constructed that express a chimeric class I molecule composed of the alpha 1 and alpha 2 domains of HLA-A2.1 and the alpha 3, transmembrane, and cytoplasmic domains of H-2Kb. Upon immunization with influenza virus, transgenic mice developed a strong A2.1Kb-restricted cytotoxic T lymphocyte (CTL) response specific for the same matrix protein epitope that serves as the dominant A2.1-restricted determinant in the equivalent human response. Fine specificity analysis of CTL clones using truncated peptides revealed strong similarity between the response repertoire of transgenic mice and that previously reported using influenza-specific A2.1-restricted CTL clones from humans. This suggests that even when considering T cell responses by different species, the alpha 1 and alpha 2 domains of the restriction element play a dominant role in determining the CTL specific repertoire. Thus, substituting the alpha 3 domain of A2.1 with a murine counterpart has permitted development of a transgenic strain that should serve as an excellent model system in studies of HLA-restricted responses.

scholarly journals Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo.

1995 ◽  
Vol 182 (5) ◽  
pp. 1201-1212 ◽  
Author(s):  
G F Rall ◽  
L Mucke ◽  
M B Oldstone
Keyword(s):  
Major Histocompatibility Complex ◽  
Transgenic Mice ◽  
Blood Brain Barrier ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Brain Barrier ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Blood Brain

Neurons have evolved strategies to evade immune surveillance that include an inability to synthesize the heavy chain of the class I major histocompatibility complex (MHC), proteins that are necessary for cytotoxic T lymphocyte (CTL) recognition of target cells. Multiple viruses have taken advantage of the lack of CTL-mediated recognition and killing of neurons by establishing persistent neuronal infections and thereby escaping attack by antiviral CTL. We have expressed a class I MHC molecule (Db) in neurons of transgenic mice using the neuron-specific enolase (NSE) promoter to determine the pathogenic consequences of CTL recognition of virally infected, MHC-expressing central nervous system (CNS) neurons. The NSE-Db transgene was expressed in H-2b founder mice, and transgene-derived messenger RNA was detected by reverse transcriptase-polymerase chain reaction in transgenic brains from several lines. Purified primary neurons from transgenic but not from nontransgenic mice adhered to coverslips coated with a conformation-dependent monoclonal antibody directed against the Dv molecule and presented viral peptide to CTL in an MHC-restricted manner, indicating that the Db molecule was expressed on transgenic neurons in a functional form. Transgenic mice infected with the neurotropic lymphocytic choriomeningitis virus (LCMV) and given anti-LCMV, MHC-restricted CTL displayed a high morbidity and mortality when compared with controls receiving MHC-mismatched CTL or expressing alternative transgenes. After CTL transfer, transgenic brains showed an increased number of CD8+ cells compared with nontransgenic controls as well as an increased rate of clearance of infectious virus from the CNS. Additionally, an increase in blood-brain barrier permeability was detected during viral clearance in NSE-Db transgenic mice and lasted several months after clearance of virus from neurons. In contrast, LCMV-infected, nontransgenic littermates and mice expressing other gene products from the NSE promoter showed no CNS disease, no increased intraparenchymal CTL, and no blood-brain barrier damage after the adoptive transfer of antiviral CTL. Our study indicates that viral infections and CTL-CNS interactions may induce blood-brain barrier disruptions and neurologic disease by a "hit-and-run" mechanism, triggering a cascade of pathogenic events that proceeds in the absence of continual viral stimulation.

scholarly journals T cell receptor genes in a series of class I major histocompatibility complex-restricted cytotoxic T lymphocyte clones specific for a Plasmodium berghei nonapeptide: implications for T cell allelic exclusion and antigen-specific repertoire.

1991 ◽  
Vol 174 (6) ◽  
pp. 1371-1383 ◽  
Author(s):  
J L Casanova ◽  
P Romero ◽  
C Widmann ◽  
P Kourilsky ◽  
J L Maryanski
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Lymphocyte ◽  
Plasmodium Berghei ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Allelic Exclusion ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Histocompatibility Complex

We report here the first extensive study of a T cell repertoire for a class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) response. We have found that the T cell receptors (TCRs) carried by 28 H-2Kd-restricted CTL clones specific for a single Plasmodium berghei circumsporozoite nonapeptide are highly diverse in terms of V alpha, J alpha, and J beta segments and aminoacid composition of the junctional regions. However, despite this extensive diversity, a high proportion of the TCRs contain the same V beta segment. These results are in contrast to most previously reported T cell responses towards class II MHC-peptide complexes, where the TCR repertoires appeared to be much more limited. In our study, the finding of a dominant V beta in the midst of otherwise highly diverse TCRs suggests the importance of the V beta segment in shaping the T cell repertoire specific for a given MHC-peptide complex. As an additional finding, we observed that nearly all clones have rearranged both TCR alpha loci. Moreover, as many as one-third of the CTL clones that we analyzed apparently display two productive alpha rearrangements. This argues against a regulated model of sequential recombination at the alpha locus and consequently raises the question of whether allelic exclusion of the TCR alpha chain is achieved at all.

scholarly journals Escape in One of Two Cytotoxic T-Lymphocyte Epitopes Bound by a High-Frequency Major Histocompatibility Complex Class I Molecule, Mamu-A*02: a Paradigm for Virus Evolution and Persistence?

2002 ◽  
Vol 76 (22) ◽  
pp. 11623-11636 ◽  
Author(s):  
Thorsten U. Vogel ◽  
Thomas C. Friedrich ◽  
David H. O'Connor ◽  
William Rehrauer ◽  
Elizabeth J. Dodds ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecule ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT It is now accepted that an effective vaccine against AIDS must include effective cytotoxic-T-lymphocyte (CTL) responses. The simian immunodeficiency virus (SIV)-infected rhesus macaque is the best available animal model for AIDS, but analysis of macaque CTL responses has hitherto focused mainly on epitopes bound by a single major histocompatibility complex (MHC) class I molecule, Mamu-A*01. The availability of Mamu-A*01-positive macaques for vaccine studies is therefore severely limited. Furthermore, it is becoming clear that different CTL responses are able to control immunodeficiency virus replication with varying success, making it a priority to identify and analyze CTL responses restricted by common MHC class I molecules other than Mamu-A*01. Here we describe two novel epitopes derived from SIV, one from Gag (Gag71-79 GY9), and one from the Nef protein (Nef159-167 YY9). Both epitopes are bound by the common macaque MHC class I molecule, Mamu-A*02. The sequences of these two eptiopes are consistent with the molecule's peptide-binding motif, which we have defined by elution of natural ligands from Mamu-A*02. Strikingly, we found evidence for the selection of escape variant viruses by CTL specific for Nef159-167 YY9 in 6 of 6 Mamu-A*02-positive animals. In contrast, viral sequences encoding the Gag71-79 GY9 epitope remained intact in each animal. This situation is reminiscent of Mamu-A*01-restricted CTL that recognize Tat28-35 SL8, which reproducibly selects for escape variants during acute infection, and Gag181-189 CM9, which does not. Differential selection by CTL may therefore be a paradigm of immunodeficiency virus infection.

scholarly journals Definition of Five New Simian Immunodeficiency Virus Cytotoxic T-Lymphocyte Epitopes and Their Restricting Major Histocompatibility Complex Class I Molecules: Evidence for an Influence on Disease Progression

2000 ◽  
Vol 74 (16) ◽  
pp. 7400-7410 ◽  
Author(s):  
David T. Evans ◽  
Peicheng Jing ◽  
Todd M. Allen ◽  
David H. O'Connor ◽  
Helen Horton ◽  
...  
Keyword(s):  
Disease Progression ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
Class I ◽  
Ctl Epitopes ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Mhc Class I Molecules

ABSTRACT Simian immunodeficiency virus (SIV) infection of the rhesus macaque is currently the best animal model for AIDS vaccine development. One limitation of this model, however, has been the small number of cytotoxic T-lymphocyte (CTL) epitopes and restricting major histocompatibility complex (MHC) class I molecules available for investigating virus-specific CTL responses. To identify new MHC class I-restricted CTL epitopes, we infected five members of a family of MHC-defined rhesus macaques intravenously with SIV. Five new CTL epitopes bound by four different MHC class I molecules were defined. These included two Env epitopes bound by Mamu-A*11 and -B*03 and three Nef epitopes bound by Mamu-B*03, -B*04, and -B*17. All four restricting MHC class I molecules were encoded on only two haplotypes (b or c). Interestingly, resistance to disease progression within this family appeared to be associated with the inheritance of one or both of these MHC class I haplotypes. Two individuals that inherited haplotypes b and cseparately survived for 299 and 511 days, respectively, while another individual that inherited both haplotypes survived for 889 days. In contrast, two MHC class I-identical individuals that did not inherit either haplotype rapidly progressed to disease (survived <80 days). Since all five offspring were identical at their Mamu-DRBloci, MHC class II differences are unlikely to account for their patterns of disease progression. These results double the number of SIV CTL epitopes defined in rhesus macaques and provide evidence that allelic differences at the MHC class I loci may influence rates of disease progression among AIDS virus-infected individuals.

scholarly journals Enhanced Intracellular Dissociation of Major Histocompatibility Complex Class I–associated Peptides: A Mechanism for Optimizing the Spectrum of Cell Surface–Presented Cytotoxic T Lymphocyte Epitopes

1997 ◽  
Vol 185 (8) ◽  
pp. 1403-1412 ◽  
Author(s):  
Alice J.A.M. Sijts ◽  
Eric G. Pamer
Keyword(s):  
Endoplasmic Reticulum ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
T Lymphocyte ◽  
Half Life ◽  
Cytotoxic T Lymphocyte ◽  
Class I ◽  
Histocompatibility Complex ◽  
Infected Cells ◽  
Mhc Class I Molecules

Association of antigenic peptides with newly synthesized major histocompatibility complex (MHC) class I molecules occurs in the endoplasmic reticulum and is a critical early step for the initiation of cytotoxic T lymphocyte (CTL)-mediated immune defenses. Pathogen-derived peptides compete with a plethora of endogenous peptides for MHC class I grooves. We find that two H2-Kd–restricted peptides, which derive from the Listeria monocytogenes p60 antigen, accumulate in infected cells with different kinetics. Although competition assays suggest that both epitopes are bound with equivalent affinity, they dissociate from MHC class I molecules at markedly different rates. p60 217-225 forms complexes with H2-Kd with a half-life &gt;6 h, while p60 449-457 dissociates from H2-Kd with a half-life of ∼1 h. We find that p60 449-457–H2-Kd complexes retained intracellularly with brefeldin A have a half-life of 30 min, and thus are less stable than surface complexes. While peptide dissociation from retained MHC class I molecules is enhanced, retained H2-Kd molecules maintain a remarkable capacity to bind new T cell epitopes. We find that intracellular H2-Kd molecules can bind new CTL epitopes for up to 3 h after their synthesis. Our studies provide a glimpse of peptide interaction with MHC class I molecules in the endoplasmic reticulum/proximal Golgi complex of intact, infected cells. We propose that the increased intracellular lability of peptide–MHC class I complexes may function to optimize the spectrum of peptides presented to T lymphocytes during cellular infection.

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