scholarly journals Immunogenicity and tolerogenicity of self-major histocompatibility complex peptides.

1990 ◽  
Vol 172 (5) ◽  
pp. 1341-1346 ◽  
Author(s):  
G Benichou ◽  
P A Takizawa ◽  
P T Ho ◽  
C C Killion ◽  
C A Olson ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Class Ii ◽  
Class I ◽  
Major Histocompatibility ◽  
Autoreactive T Cells ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Self Tolerance

Mechanisms involved in self-antigen processing and presentation are crucial in understanding the induction of self-tolerance in the thymus. We examined the immunogenicity of determinants from major histocompatibility complex (MHC) molecules that are expressed in the thymus and have tested peptides derived from the polymorphic regions of class I and class II molecules. We found that two peptides corresponding to NH2 termini of the class II alpha and beta chains (Ak alpha 1-18 and Ak beta 1-16) could bind to self-Ak molecules with high affinity and, surprisingly, were immunogenic in that they could elicit strong proliferative T cell responses in B10.A mice (Ak, Ek). Neonatal injection of peptide Ak beta 1-16 resulted in complete unresponsiveness to this peptide at 8 wk of age showing that these T cells were susceptible to tolerance induction. We have also tested certain class I MHC peptides and showed that some can interact efficiently with class II MHC peptides to induce an autoreactive T cell proliferative response. Among these class I peptides is one (Dd 61-85) that has the capacity to bind to self-Ia without being immunogenic, and therefore represents an MHC determinant that had induced thymic self-tolerance. We conclude that some self-MHC molecules can be processed into peptides that can be presented in the context of intact class II molecules at the surface of antigen-presenting cells. Autoreactive T cells recognizing optimally processed self-peptide/MHC complexes are eliminated during development, whereas other potentially autoreactive T cells escape clonal inactivation or deletion. Incomplete tolerance to self-antigens enriches the T cell repertoire despite the fact that such T cells may eventually become involved in autoimmune disease.

scholarly journals Greatly reduced lymphoproliferation in lpr mice lacking major histocompatibility complex class I.

1995 ◽  
Vol 181 (2) ◽  
pp. 641-648 ◽  
Author(s):  
M A Maldonado ◽  
R A Eisenberg ◽  
E Roper ◽  
P L Cohen ◽  
B L Kotzin
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Class Ii ◽  
T Cell Subsets ◽  
Cell Surface Receptor ◽  
Class I ◽  
Major Histocompatibility ◽  
Gamma Delta ◽  
Histocompatibility Complex

Mice homozygous for the lpr gene have a defect in fas (CD95), a cell surface receptor that belongs to the tumor necrosis factor receptor family and that mediates apoptosis. This genetic abnormality results in lymphoproliferation characterized by the accumulation of CD4-CD8- (double negative [DN]) T cells, autoantibody production, and background strain-dependent, end-organ disease. Our previous results suggested that major histocompatibility complex (MHC) class I may be involved in the development of DN cells. To test this hypothesis, we derived C57BL/6-lpr/lpr (B6/lpr) mice that were deficient for the beta 2-microglobulin gene (beta 2m lpr) and had no detectable class I expression. At 6 mo of age, compared with B6/lpr littermates with normal class I genes, these mice showed greatly reduced lymphadenopathy, mostly due to a dramatic decrease in the number of DN cells. Significant changes in the percentage of other T cell subsets were noted, but only gamma/delta+ T cells showed a marked increase in both percentage and absolute numbers. Analysis of T cell receptor V beta expression of the remaining DN T cells in beta 2m -lpr mice showed a shift to a CD4-like repertoire from a CD8-like repertoire in control B6/lpr mice, indicating that a small MHC class II selected DN population was unmasked in lpr mice lacking class I. We also found that the production of immunoglobulin G (IgG) autoantibodies (antichromatin and anti-single stranded DNA), total IgG and IgG2a, but not total IgM or IgM rheumatoid factor, was significantly reduced in the beta 2m -lpr mice. This work suggests that >90% of DN T cells in lpr mice are derived from the CD8 lineage and are selected on class I. However, a T cell subset selected on class II and T cells expressing gamma/delta are also affected by the lpr defect and become minor components of the aberrant DN population.

scholarly journals Thymic selection of CD8+ single positive cells with a class II major histocompatibility complex-restricted receptor.

1994 ◽  
Vol 180 (1) ◽  
pp. 25-34 ◽  
Author(s):  
J Kirberg ◽  
A Baron ◽  
S Jakob ◽  
A Rolink ◽  
K Karjalainen ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Cell Receptor ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Alpha Beta

We describe mice that express a transgenic T cell receptor alpha/beta (TCR-alpha/beta) specific for peptide 111-119 from influenza hemagglutinin presented by I-Ed class II major histocompatibility complex (MHC) molecules. The transgenic TCR is expressed on CD4+8- as well as CD4-8+ mature T cells even in mice that are deficient in rearrangement or do not express endogenous TCR-alpha genes. The CD4-8+ T cells require I-Ed class II MHC molecules for positive selection and can be activated to proliferate and to kill by I-Ed molecules presenting the relevant peptide. Full maturation of these cells, however, also requires the presence of class I MHC molecules. The results are compatible with the notion that T cell maturation requires multiple receptor-ligand interactions and establish an exception to the rule that class II-restricted TCRs are exclusively expressed by mature CD4+8- cells.

scholarly journals The Role of Peptides in T Cell Alloreactivity Is Determined by Self–Major Histocompatibility Complex Molecules

2000 ◽  
Vol 191 (5) ◽  
pp. 805-812 ◽  
Author(s):  
Reinhard Obst ◽  
Nikolai Netuschil ◽  
Karsten Klopfer ◽  
Stefan Stevanović ◽  
Hans-Georg Rammensee
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Complex Molecules ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Alloreactive T Cells

By analyzing T cell responses against foreign major histocompatibility complex (MHC) molecules loaded with peptide libraries and defined self- and viral peptides, we demonstrate a profound influence of self-MHC molecules on the repertoire of alloreactive T cells: the closer the foreign MHC molecule is related to the T cell's MHC, the higher is the proportion of peptide-specific, alloreactive (“allorestricted”) T cells versus T cells recognizing the foreign MHC molecule without regard to the peptide in the groove. Thus, the peptide repertoire of alloreactive T cells must be influenced by self-MHC molecules during positive or negative thymic selection or peripheral survival, much like the repertoire of the self-restricted T cells. In consequence, allorestricted, peptide-specific T cells (that are of interest for clinical applications) are easier to obtain if T cells and target cells express related MHC molecules.

scholarly journals Selective enrichment of major histocompatibility complex class II-specific autoreactive T cells in the thymic Thy0 subset.

1993 ◽  
Vol 177 (5) ◽  
pp. 1429-1437 ◽  
Author(s):  
I Kariv ◽  
R R Hardy ◽  
K Hayakawa
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
Class Ii ◽  
Cd4 T Cell ◽  
Complex Class ◽  
Autoreactive T Cells ◽  
Cell Hybrids ◽  
Histocompatibility Complex

We show here a unique enrichment of autoreactive T cells in the CD4+ mouse thymic subset, Thy0. A single- and 10-cell AMLR (autologous mixed leukocyte reaction) assay demonstrates that more than 30% (one cell per well) and almost all (10 cells per well) Thy0 cultures from normal mice exhibit reactivity specific to autologous cells, resulting in induction of interleukin 3 secretion. In contrast, no other mature thymic or splenic CD4+ T cell subsets showed such a high frequency. The majority of this AMLR reactivity in the Thy0 subset is accounted for by reactivity with self-major histocompatibility complex class II. Furthermore, antigenic selection in generating Thy0 subset is suggested by studies with T cell hybrids from a T cell receptor (TCR) V beta transgenic mouse line, 2B4 beta EH. TCR V-gene analysis of T cell hybrids revealed that those from Thy0, half of which responded to self-class II, consisted predominantly of cells that expressed endogenous TCR V beta s alone (without the transgene), unlike hybrids generated from peripheral naive T cells. Thus, we suggest that the presence of Thy0 results from selective stimulation of cells expressing TCR with sufficient affinity for autoantigens in the thymic CD4+ T cell repertoire.

scholarly journals Specificity of T cell clones for antigen and autologous major histocompatibility complex products determines specificity for foreign major histocompatibility complex products.

1983 ◽  
Vol 158 (2) ◽  
pp. 428-437 ◽  
Author(s):  
S R Abromson-Leeman ◽  
H Cantor
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Molecular Mimicry ◽  
Class Ii ◽  
Major Histocompatibility ◽  
T Cell Clones ◽  
Complex Products ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Cell Clones

We have analyzed a panel of T cell clones that corecognize defined epitopes of the insulin molecule in association with Ia for their patterns of recognition of alloantigens. A striking correlation is observed between recognition of the I-Ab gene product and cow insulin alpha loop and recognition of I-Eu of the PL/J haplotype. These results are consistent with the notion that reactions to foreign major histocompatibility complex (MHC) products reflect molecular mimicry by foreign class II antigens of 'physiologic' complexes formed by autologous class II MHC molecules and antigen.

scholarly journals Xenogeneic human anti-mouse T cell responses are due to the activity of the same functional T cell subsets responsible for allospecific and major histocompatibility complex-restricted responses.

1983 ◽  
Vol 157 (2) ◽  
pp. 720-729 ◽  
Author(s):  
S L Swain ◽  
R W Dutton ◽  
R Schwab ◽  
J Yamamoto
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Subsets ◽  
Class I ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc Antigens ◽  
Histocompatibility Complex ◽  
Mouse Class

Human T cells respond strongly to mouse major histocompatibility complex (MHC) antigens. The response is directed predominantly to the polymorphic determinants of the MHC antigens and there is little or no response to the nonpolymorphic determinants or to non-MHC antigens. Human cytotoxic T lymphocytes (CTL) are generated specific for the mouse class I MHC antigens and the CTL effectors are blocked by anti-Leu-2a antisera. Human interleukin 2-producing T cells are generated specific for mouse class II antigens and their induction is blocked by anti-Leu-3a antisera. These and other considerations lead us to propose a model for the T cell receptor that provides an explanation for several of the features of T cell recognition. In this model, the recognition of the "class" (I or II) of MHC antigen is separate from the recognition of the polymorphic determinants. We suggest that the initial recognition of the conserved "class" determinants positions another domain of the receptor so that it can only engage with the part of the MHC molecule carrying the polymorphic determinants.

Myofiber Expression of Class I Major Histocompatibility Complex Accompanied by CD8+ T-cell-associated Myofiber Injury in a Case of Canine Polymyositis

2002 ◽  
Vol 39 (4) ◽  
pp. 512-515 ◽  
Author(s):  
T. Morita ◽  
A. Shimada ◽  
S. Yashiro ◽  
T. Takeuchi ◽  
Y. Hikasa ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Plasma Cells ◽  
Early Stage ◽  
Cd8 T Cell ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

A 7-year-old female Labrador Retriever dog showed extreme muscular weakness, muscle wasting, dysbasia, and mild dysphagia. An elevated value of creatine kinase (335 IU/liter) in the serum was detected. Electromyographic findings included increased insertional activity, fibrillation potentials, and bizarre high-frequency repetitive potentials. Histopathologic examination of skeletal muscles revealed myofiber necrosis and phagocytosis, regeneration of myofibers, and perivascular, perimysial, and endomysial infiltrations of lymphocytes, macrophages and plasma cells. Immunohistochemical evaluation demonstrated that infiltrative cells in the early stage of myositis were CD8+ T-cells and that an increased expression of major histocompatibility complex (MHC) class I was apparent on the surface of nonnecrotic muscle fibers. In contrast, many CD3+ cells (T cells) and HLA-DR-positive macrophages and B lymphocytes were found in the severely affected areas. These results suggest that both expression of MHC class I and CD8+ T-cell infiltration may play an important role in initiation of myositis. These histopathologic findings resemble those reported in naturally occurring polymyositis in humans.

scholarly journals Clone-specific T cell receptor antagonists of major histocompatibility complex class I-restricted cytotoxic T cells.

1993 ◽  
Vol 177 (6) ◽  
pp. 1541-1550 ◽  
Author(s):  
S C Jameson ◽  
F R Carbone ◽  
M J Bevan
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Class I ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Histocompatibility Complex ◽  
T Cell Clone

A previous report showed that the proliferative response of helper T cells to class II major histocompatibility complex (MHC)-restricted antigens can be inhibited by analogues of the antigen, which act as T cell receptor (TCR) antagonists. Here we define and analyze peptide variants that antagonize various functions of class I MHC-restricted cytotoxic T lymphocyte (CTL) clones. Of 64 variants at individual TCR contact sites of the Kb-restricted octamer peptide ovalbumin257-264 (OVAp), a very high proportion (40%) antagonized lysis by three OVAp-specific CTL clones. This effect was highly clone specific, since many antagonists for one T cell clone have differential effects on another. We show that this inhibition of CTL function is not a result of T cell-T cell interaction, precluding veto-like phenomena as a mechanism for antagonism. Moreover, we present evidence for direct interaction between the TCR and antagonist-MHC complexes. In further analysis of the T cell response, we found that serine esterase release and cytokine production are susceptible to TCR antagonism similarly to lysis. Ca2+ flux, an early event in signaling, is also inhibited by antagonists but may be more resistant to the antagonist effect than downstream responses.

scholarly journals Sequences in both class II major histocompatibility complex alpha and beta chains contribute to the binding of the superantigen toxic shock syndrome toxin 1.

1992 ◽  
Vol 175 (5) ◽  
pp. 1301-1305 ◽  
Author(s):  
N S Braunstein ◽  
D A Weber ◽  
X C Wang ◽  
E O Long ◽  
D Karp
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Toxic Shock Syndrome ◽  
Cell Receptor ◽  
Class Ii ◽  
Major Histocompatibility ◽  
Toxic Shock ◽  
Mhc Molecules ◽  
Histocompatibility Complex ◽  
Toxic Shock Syndrome Toxin

Class II major histocompatibility complex (MHC) molecules present peptides derived from processed antigen to antigen-specific CD4-positive T cells. In addition, class II molecules bind with high affinity another class of antigens, termed superantigens. T cell stimulation by superantigens depends almost exclusively on the V beta segment expressed by the T cell receptor (TCR). Mapping of the superantigen binding site on class II molecules should provide valuable information on how MHC and TCR molecules interact. Recombinant mouse I-A class II molecules expressed on transfected L cells were analyzed for their ability to bind the toxic shock syndrome toxin 1. Polymorphic residues in the alpha helices of both the alpha and beta chains of I-A contributed to quantitative toxin binding, suggesting that the toxin binds to either a combinatorial or a conformational site on class II MHC molecules.

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