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 Novel Role of CD8+ T Cells and Major Histocompatibility Complex Class I Genes in the Generation of Protective CD4+ Th1 Responses during Retrovirus Infection in Mice

2002 ◽  
Vol 76 (16) ◽  
pp. 7942-7948 ◽  
Author(s):  
Karin E. Peterson ◽  
Ingunn Stromnes ◽  
Ron Messer ◽  
Kim Hasenkrug ◽  
Bruce Chesebro
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Mhc Class Ii ◽  
T Cell Responses ◽  
Class I ◽  
Major Histocompatibility ◽  
Cell Responses ◽  
Histocompatibility Complex

ABSTRACT CD4+ Th1 responses to virus infections are often necessary for the development and maintenance of virus-specific CD8+ T-cell responses. However, in the present study with Friend murine retrovirus (FV), the reverse was also found to be true. In the absence of a responder H-2b allele at major histocompatibility complex (MHC) class II loci, a single H-2Db MHC class I allele was sufficient for the development of a CD4+ Th1 response to FV. This effect of H-2Db on CD4+ T-cell responses was dependent on CD8+ T cells, as demonstrated by depletion studies. A direct effect of CD8+ T-cell help in the development of CD4+ Th1 responses to FV was also shown in vaccine studies. Vaccination of nonresponder H-2a/a mice induced FV-specific responses of H-2Dd -restricted CD8+ cytotoxic T lymphocytes (CTL). Adoptive transfer of vaccine-primed CD8+ T cells to naive H-2a/a mice prior to infection resulted in the generation of FV-specific CD4+ Th1 responses. This novel helper effect of CD8+ T cells could be an important mechanism in the development of CD4+ Th1 responses following vaccinations that induce CD8+ CTL responses. The ability of MHC class I genes to facilitate CD4+ Th1 development could also be considerable evolutionary advantage by allowing a wider variety of MHC genotypes to generate protective immune responses against intracellular pathogens.

scholarly journals Requirement for CD8-major histocompatibility complex class I interaction in positive and negative selection of developing T cells.

1992 ◽  
Vol 176 (1) ◽  
pp. 89-97 ◽  
Author(s):  
N Killeen ◽  
A Moriarty ◽  
H S Teh ◽  
D R Littman
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Negative Selection ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Mhc Class I Molecules ◽  
Selection Of

The interaction of the T cell surface glycoprotein CD8 with major histocompatibility complex (MHC) class I molecules on target cells is required for effective T cell activation. Mutations in the alpha 3 domain of the MHC class I molecule can disrupt binding to CD8, yet leave antigen presentation unaffected. Here we show that such a mutation can interfere with positive and negative selection of T cells bearing T cell receptors (TCRs) that interact specifically with the mutant class I molecule. Autoreactive T cells in male mice expressing a transgenic TCR specific for the male antigen H-Y and H-2Db were not deleted in the context of a transgenic Db molecule bearing a mutation at residue 227. Similarly, CD8+ cells were not positively selected in female mice expressing both the TCR and mutant class I transgenes. Endogenous MHC class I molecules were competent to bind CD8, but were unable to rescue the defect, indicating a requirement for coordinate recognition of antigen/MHC by a complex of the TCR and CD8 coreceptor for both positive and negative selection of thymocytes.

scholarly journals Efficient Targeting of Protein Antigen to the Dendritic Cell Receptor DEC-205 in the Steady State Leads to Antigen Presentation on Major Histocompatibility Complex Class I Products and Peripheral CD8+ T Cell Tolerance

2002 ◽  
Vol 196 (12) ◽  
pp. 1627-1638 ◽  
Author(s):  
Laura Bonifaz ◽  
David Bonnyay ◽  
Karsten Mahnke ◽  
Miguel Rivera ◽  
Michel C. Nussenzweig ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Steady State ◽  
T Cell ◽  
Mhc Class I ◽  
Cd8 T Cells ◽  
Class I ◽  
Histocompatibility Complex ◽  
Dc Maturation

To identify endocytic receptors that allow dendritic cells (DCs) to capture and present antigens on major histocompatibility complex (MHC) class I products in vivo, we evaluated DEC-205, which is abundant on DCs in lymphoid tissues. Ovalbumin (OVA) protein, when chemically coupled to monoclonal αDEC-205 antibody, was presented by CD11c+ lymph node DCs, but not by CD11c− cells, to OVA-specific, CD4+ and CD8+ T cells. Receptor-mediated presentation was at least 400 times more efficient than unconjugated OVA and, for MHC class I, the DCs had to express transporter of antigenic peptides (TAP) transporters. When αDEC-205:OVA was injected subcutaneously, OVA protein was identified over a 4–48 h period in DCs, primarily in the lymph nodes draining the injection site. In vivo, the OVA protein was selectively presented by DCs to TCR transgenic CD8+ cells, again at least 400 times more effectively than soluble OVA and in a TAP-dependent fashion. Targeting of αDEC-205:OVA to DCs in the steady state initially induced 4–7 cycles of T cell division, but the T cells were then deleted and the mice became specifically unresponsive to rechallenge with OVA in complete Freund's adjuvant. In contrast, simultaneous delivery of a DC maturation stimulus via CD40, together with αDEC-205:OVA, induced strong immunity. The CD8+ T cells responding in the presence of agonistic αCD40 antibody produced large amounts of interleukin 2 and interferon γ, acquired cytolytic function in vivo, emigrated in large numbers to the lung, and responded vigorously to OVA rechallenge. Therefore, DEC-205 provides an efficient receptor-based mechanism for DCs to process proteins for MHC class I presentation in vivo, leading to tolerance in the steady state and immunity after DC maturation.

scholarly journals A Common Inhibitory Receptor for Major Histocompatibility Complex Class I Molecules on Human Lymphoid and Myelomonocytic Cells

1997 ◽  
Vol 186 (11) ◽  
pp. 1809-1818 ◽  
Author(s):  
Marco Colonna ◽  
Francisco Navarro ◽  
Teresa Bellón ◽  
Manuel Llano ◽  
Pilar García ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
B Cells ◽  
Mhc Class I ◽  
Killer Cell ◽  
Class I ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Myelomonocytic Cells ◽  
Mhc Class I Molecules

Natural killer (NK) cell–mediated lysis is negatively regulated by killer cell inhibitory receptors specific for major histocompatibility complex (MHC) class I molecules. In this study, we characterize a novel inhibitory MHC class I receptor of the immunoglobulin-superfamily, expressed not only by subsets of NK and T cells, but also by B cells, monocytes, macrophages, and dendritic cells. This receptor, called Ig-like transcript (ILT)2, binds MHC class I molecules and delivers a negative signal that inhibits killing by NK and T cells, as well as Ca2+ mobilization in B cells and myelomonocytic cells triggered through the B cell antigen receptor and human histocompatibility leukocyte antigens (HLA)–DR, respectively. In addition, myelomonocytic cells express receptors homologous to ILT2, which are characterized by extensive polymorphism and might recognize distinct HLA class I molecules. These results suggest that diverse leukocyte lineages have adopted recognition of self–MHC class I molecules as a common strategy to control cellular activation during an immune response.

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.

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 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 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 Major histocompatibility complex class I presentation of peptides derived from soluble exogenous antigen by a subset of cells engaged in phagocytosis.

1995 ◽  
Vol 182 (3) ◽  
pp. 841-851 ◽  
Author(s):  
C Reis e Sousa ◽  
R N Germain
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Mhc Class I ◽  
Class I ◽  
Soluble Antigen ◽  
Major Histocompatibility ◽  
Particle Uptake ◽  
Histocompatibility Complex ◽  
Exogenous Antigen ◽  
Mhc Class I Molecules

Major histocompatibility complex (MHC) class I molecules generally present peptides derived from cytoplasmic proteins, but recent reports have suggested that macrophages (M phi) may be uniquely able to present exogenous antigens via these molecules, and that particle-associated antigens show a marked increase in the efficiency of such presentation. We confirm here that particle uptake by M phi permits exogenous ovaalbumin (OVA) to gain access to the endogenous class I processing pathway, an event that occurs rarely, if at all, in the absence of phagocytic stimuli. Presentation of soluble protein antigens by MHC class I molecules, however, is not limited to M phi, nor is direct coupling of antigen to the particle required. A variety of unconjugated particles promoted presentation of simultaneously offered soluble OVA to Kb-restricted T cells by both M phi and non-M phi antigen-presenting cells (APC), provided the latter could phagocytose the particles. Enhancement of presentation by phagocytic stimuli could not be explained by greater delivery of soluble antigen to endosomal compartments because such stimuli did not increase soluble tracer accumulation, nor did they improve presentation of OVA to an MHC class II-restricted T cell hybridoma. OVA presentation induced by cophagocytosis of particles and free antigen was nevertheless very inefficient in comparison to presentation of OVA peptide, and even modest responses required high concentrations of protein and particles. Furthermore, only a fraction of APC exposed to OVA and particles were lysed by anti-OVA cytotoxic T lymphocytes, despite virtually all cells showing OVA accumulation, particle uptake, and Kb expression. Titration experiments were most consistent with a model in which, by disrupting membrane integrity, phagocytic overload ("indigestion") allows escape of OVA into the cytosol of some APC, rather than with a model in which phagocytosis activates a novel antigen processing pathway that has evolved to permit class I loading of exogenous antigen. These data suggest caution in the development of vaccine strategies based on use of particle conjugates for elicitation of CD8+ T cell immunity, but, at the same time, may be relevant to understanding class I-restricted responses to some intracellular pathogens normally resident in membrane-bound vesicles.

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