scholarly journals Major Histocompatibility Complex Haplotype Determines hsp70-Dependent Protection against Measles Virus Neurovirulence

2009 ◽  
Vol 83 (11) ◽  
pp. 5544-5555 ◽  
Author(s):  
Thomas Carsillo ◽  
Mary Carsillo ◽  
Zachary Traylor ◽  
Päivi Rajala-Schultz ◽  
Phillip Popovich ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Measles Virus ◽  
Protective Role ◽  
Major Histocompatibility ◽  
Major Histocompatibility Complex Haplotype ◽  
Brain Infection ◽  
Histocompatibility Complex ◽  
The Impact

ABSTRACT In vitro studies show that hsp70 promotes gene expression for multiple viral families, although there are few reports on the in vivo significance of virus-hsp70 interaction. Previously we showed that hsp70-dependent stimulation of Edmonston measles virus (Ed MeV) transcription caused an increased cytopathic effect and mortality in transgenic hsp70-overexpressing C57BL/6 mice (H-2 b ). The response to MeV infection is influenced by the major histocompatibility complex haplotype; H-2 d mice are resistant to brain infection due to robust antiviral immune responses, whereas H-2 b mice are susceptible due to deficiencies in this response. We therefore tested the hypothesis that the outcome of MeV-hsp70 interaction may be dependent upon the host H-2 haplotype. The impact of selective neuronal hsp70 overexpression on Ed MeV brain infection was tested with congenic C57BL/10 H-2 d neonatal mice. In this context, hsp70 overexpression conferred complete protection against virus-induced mortality, compared to >30% mortality in nontransgenic mice. Selective depletion of T-cell populations showed that transgenic mice exhibit a diminished reliance on T cells for protection. Brain transcript analysis indicated enhanced innate immune activation and signaling through Toll-like receptors 2 and 4 at early times postinfection for transgenic infected mice relative to those for nontransgenic infected mice. Collectively, results suggest that hsp70 can enhance innate antiviral immunity through Toll-like receptor signaling, supporting a protective role for physiological responses that enhance tissue levels of hsp70 (e.g., fever), and that the H-2 haplotype determines the effectiveness of this response.

Abstract 124: Parthenogenetic Stem Cell-derived Cardiomyocytes Express Major Histocompatibility Complex-I only after Inflammatory Stimulation

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Satish Galla ◽  
Michael Didie ◽  
Vijayakumar Muppala ◽  
Ralf Dressel ◽  
Wolfram Hubertus Zimmermann
Keyword(s):  
Major Histocompatibility Complex ◽  
Heart Muscle ◽  
Immunological Response ◽  
Type I ◽  
Major Histocompatibility ◽  
Adrenergic Stimulation ◽  
Mhc I ◽  
Histocompatibility Complex

Background: Pluripotent parthenogenetic stem cells (PSCs) can be directed towards a cardiac fate and utilized in tissue engineered heart repair. In vivo applications of tissue engineered allografts are compromised by expression of mismatching major histocompatibility complex proteins (MHC; encoded in the murine H2 locus). Here we investigated whether PSC-derived cardiomyocytes (CM) express MHC-I. Methods: Mouse PSCs (A3-line from B6D2F1 strain with haploidentical H2K d -locus) expressing a CM-specific neomycin-resistance and GFP were differentiated and purified for CM by addition of G418 (85% purity by FACS for actinin). To simulate heart muscle biology in vitro, we made use of engineered heart muscle (EHM) constructed from PSC-derived CM (75%), growth-inhibited murine embryonic fibroblasts (MEF (25%); NMRI mice), and collagen type I. MHC class-I H2K d (MHC-I) expression was assessed on CM and Non myocytes before EHM assembly and from enzymatically digested EHMs (cultured for 10 days) by FACS. Interferon gamma (IFNγ) was added for 48 h to stimulate MHC-I expression. As a reference, we investigated MHC-I expression in CM from neonatal mice and adult mouse hearts by FACS and by immunofluorescence staining. Results: EHM showed a positive ionotropic response to beta-adrenergic stimulation which could be reduced by muscarinergic stimulation. A3-CM, in contrast to Non myocytes, showed negligible expression of MHC-I (1±0.5% vs. 60±10% positive cells; n=3). EHM culture did not change MHC-I expression in CM. IFNγ treatment resulted in a marked increase of MHC-I-expression in CM monolayer culture (40±6%; n=3) and in EHM (30±8%; n=3). For comparison, 30% (n=2) neonatal CM expressed MHC-I while MHC-I was not detectable in adult CM. Conclusion: PSC-derived CM show a similarly low expression of MHC-I as adult CM and respond with MHC-I upregulation to IFNγ stimulation. This suggests a mature immunological response in PSC-CM with important implications for in vivo applications, i.e., MHC-I matching will likely be a prerequisite for successful allografting of PSC-EHM.

scholarly journals Disease inhibition by major histocompatibility complex binding peptide analogues of disease-associated epitopes: more than blocking alone.

1992 ◽  
Vol 176 (3) ◽  
pp. 667-677 ◽  
Author(s):  
M H Wauben ◽  
C J Boog ◽  
R van der Zee ◽  
I Joosten ◽  
A Schlief ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Major Histocompatibility ◽  
In Vitro Proliferation ◽  
Histocompatibility Complex ◽  
Disease Induction ◽  
Immunomodulatory Peptides ◽  
Peptide Analogues

Peptide analogues of disease-associated epitopes were studied for inhibition of experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) in Lewis rats. EAE- and AA-associated analogues were selected as competitors because of their in vitro inhibitory activity on proliferation of encephalitogenic and arthritogenic T cells. Although the EAE-associated competitor had a superior major histocompatibility complex (MHC) binding affinity, the AA-associated competitor was a better inhibitor of the in vitro proliferation of arthritogenic T cells. Furthermore, although in vivo EAE was inhibited by both competitors, AA was only inhibited by the AA-associated competitor. Remarkably, in contrast to what was expected of a regular MHC competitor peptide, the AA-associated peptide analogue also prevented AA upon immunization before disease induction and appeared to induce T cell responses that crossreacted with the original disease-associated epitope. Therefore, it is concluded that antigen-specific regulatory mechanisms were involved in synergy with MHC competition. The integration of both qualities into a single "competitor-modulator" analogue peptide may lead to the development of novel, more effective, disease-specific immunomodulatory peptides.

scholarly journals Major histocompatibility complex-specific prolongation of murine skin and cardiac allograft survival after in vivo depletion of V beta+ T cells.

1993 ◽  
Vol 177 (1) ◽  
pp. 35-44 ◽  
Author(s):  
J A Goss ◽  
R Pyo ◽  
M W Flye ◽  
J M Connolly ◽  
T H Hansen
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Intraperitoneal Administration ◽  
Cell Receptor ◽  
Primary Response ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Allogeneic Response

The preferential usage of certain T cell receptor (TCR) V beta genes has been well established in several major histocompatibility complex (MHC)-restricted immune responses. However, V beta usage among allogeneic responses remains unclear. Because recent findings of ours and others indicate that V beta 8 predominates in certain Ld-restricted, peptide-specific responses, we examined the V beta 8 usage in allogeneic responses to Ld. To selectively recognize the Ld molecule, cells from BALB/c-H-2dm2 (dm2), the Ld-loss mutant mouse, were stimulated in vitro or in vivo with wild-type BALB/c cells. We report here that after the intraperitoneal administration of the anti-V beta 8 monoclonal antibody (mAb) F23.1, peripheral V beta 8 T cells were depleted from dm2 mice. This in vivo depletion abrogated the ability of dm2 splenocytes to mount a primary response to Ld molecules. This abrogation was specific, since the response of V beta 8-depleted dm2 cells to Kb/Db antigens was the same as that of control nondepleted dm2 cells. Furthermore, in vivo depletion of V beta 8 cells was found to cause a dramatic prolongation of Ld-disparate skin grafts (mean survival time [MST] 22.1 +/- 2.1 vs. 10.3 +/- 1.1 d for saline-treated controls, or 10.9 +/- 1.7 d for controls treated with mAb KJ23 to V beta 17). By contrast, V beta 8 depletion had no effect on recipients grafted with haplotype-mismatched skin or single Dk-locus-disparate skin. These findings demonstrate that V beta 8+ T cells predominate in allogeneic response to Ld but not other alloantigens. The effect of V beta 8 depletion was found to be even more dramatic on recipients grafted with Ld-disparate vascularized heart transplants (MST > 100 vs. 8.6 +/- 0.5 d for controls). In total, these findings establish the efficacy of using mAb to the V beta gene family to specifically and significantly enhance the survival of allografts. The implications of detecting V beta 8 usage in both alloreactive or MHC-restricted TCR responses to the same class I molecule are discussed.

scholarly journals Role of the major histocompatibility complex in T cell activation of B cell subpopulations. lyb-5(+) and lyb-5(-) B cell subpopulations differ in their requirement for major histocompatibility complex-restricted T cell recognition

1981 ◽  
Vol 154 (2) ◽  
pp. 501-516 ◽  
Author(s):  
A Singer ◽  
PJ Morrissey ◽  
KS Hathcock ◽  
A Ahmed ◽  
I Scher ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Recognition ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Cell Subpopulations

This report has examined the requirements for T helper (T(H)) cell recognition of major histocompatibility complex (MHC) determinants expressed by B cells for the activation of unprimed Lyb-5(+) and Lyb-5(-) B cell subpopulations . The generation of primary T(H) cell-dependent plaque-forming cell responses in vitro microculture required the presence of Lyb-5(+) B cells because B cell populations that were deprived, either genetically or serologically, of the Lyb-5(+) subpopulation were not activated in these responses. Cell-mixing experiments in which A X B {arrow} A chimeric T(H) cells were mixed with purified populations of parental accessory cells and parental B cells demonstrated that the in vitro activation of Lyb-5(+) B cells did not require T(H) cell recognition of B cell MHC determinants, although it did require T(H) cell recognition of accessory cell MHC determinants . In contrast to the failure of Lyb-5(-) B cells to be activated in primary T(H) cell-dependent responses in vitro microculture, isolated populations of Lyb-5(-) B cells were triggered by T(H) cells in vivo in short-term adoptive transfer experiments . By the use of A X B {arrow} A chimeric T(H) cells and parental strain B adoptive hosts, it was possible in vivo to distinguish genetically restricted T(H) cell recognition of B cells from genetically restricted T(H) cell recognition of accessory cells. Similar to the results obtained in vitro, the activation in vivo of unfractionated (Lyb-5(+) plus Lyb-5(-)) B cell populations did not require T(H) cell recognition of B cell MHC determinants . In contrast, in the same in vivo responses activation of isolated populations of Lyb-5(-) B cells did require T(H) cell recognition of B cell MHC determinants. The most straightforward interpretation of these experiments is that T(H) cell recognition of B cell MHC determinants is required for the activation of Lyb-5(-) B cells but is not required for the activation of Lyb-5(+) B cells . To better understand why T(H) cell activation of one B cell subpopulation is genetically restricted, whereas activation of another subpopulation is not, the response of Lyb-5(+) and Lyb-5(-) B cells to the soluble activating factors present in concanavalin A-induced spleen cell supernates (Con A SN) was examined. It was observed that Lyb-5(-) B cells, as opposed to Lyb-5(+) B cells, were unable to respond in microculture to the nonspecific T(H) cell- activating factors present in Con A SN, even though they were able to nonspecifically respond under the same conditions to trinitrophenyllipopolysaccharide. It was observed that the ability of B cell subpopulations to respond to nonspecific soluble T cell factors paralleled their ability to be activated by T(H) cells in a genetically unrestricted manner. Thus, the present experiments demonstrate that activation by T(H) cells of Lyb-5(-) B cells is MHC restricted, whereas activation of Lyb-5(+) B cells is not. These experiments suggest that one possible explanation for such differences is that activation of Lyb-5(+) B cells does not require direct interaction with T(H) cells because they can be activated by soluble activation signals that T(H) cells secrete.

scholarly journals Designer Glycopeptides for Cytotoxic T Cell–based Elimination of Carcinomas

2004 ◽  
Vol 199 (5) ◽  
pp. 707-716 ◽  
Author(s):  
Yanfei Xu ◽  
Sandra J. Gendler ◽  
Alessandra Franco
Keyword(s):  
Major Histocompatibility Complex ◽  
T Cell ◽  
Large Population ◽  
Vaccination Strategy ◽  
Cytotoxic T Cell ◽  
Major Histocompatibility ◽  
Carbohydrate Antigens ◽  
Histocompatibility Complex

Tumors express embryonic carbohydrate antigens called tumor-associated carbohydrate antigens (TACA). TACA-containing glycopeptides are appealing cytotoxic T cell (CTL)-based vaccines to prevent or treat cancer because the same sugar moieties are expressed in a variety of tumors, rendering a vaccination strategy applicable in a large population. Here we demonstrate that by using glycopeptides with high affinity for the major histocompatibility complex and glycosylated in a position corresponding to a critical T cell receptor (TcR) contact, it is possible to induce anti-TACA CTL in vivo. In the current study we show that designer glycopeptides containing the Thomsen-Freidenreich (TF) antigen (β-Gal-[1→3]-α-GalNAc-O-serine) are immunogenic in vivo and generate TF-specific CTL capable of recognizing a variety of tumor cells in vitro including a MUC1-expressing tumor. The fine specificity of the TF-specific CTL repertoire indicates that the TcR recognize the glycosylated amino acid residue together with TF in a conventional major histocompatibility complex class I–restricted fashion. These results have high potential for immunotherapy against a broad range of tumors.

scholarly journals Control of rat natural killer cell-mediated allorecognition by a major histocompatibility complex region encoding nonclassical class I antigens.

1994 ◽  
Vol 180 (2) ◽  
pp. 641-651 ◽  
Author(s):  
J T Vaage ◽  
C Naper ◽  
G Løvik ◽  
D Lambracht ◽  
A Rehm ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Nk Cells ◽  
Natural Killer ◽  
Class I ◽  
F1 Hybrids ◽  
Major Histocompatibility ◽  
Histocompatibility Complex ◽  
Nonclassical Class

The ability of natural killer (NK) cells to eliminate normal allogeneic hemic cells is well established in several species including mice, rats, and humans. The controlling elements for NK susceptibility in these species map to the major histocompatibility complex (MHC), but in contrast to findings in mice and humans, the mode of inheritance is not always recessive in rats. This finding is not easily explained by the missing self and hemopoietic histocompatibility (Hh) models for NK recognition, and has led to the idea that certain alloantigens may trigger NK cell reactivity. In our in vitro system for assessing rat NK alloreactivity, we have employed target and inhibitor cells from a large panel of MHC congenic, intra-MHC recombinant and MHC mutant rat strains, as well as appropriate F1 hybrids between them, and we show the following: (a) The nonclassical class I (RT1.C) region was most important in determining the susceptibility of target cells to alloreactive NK cells in vitro. Lymphocyte susceptibility to lysis in vivo also mapped to the C region, which supports the concept that the in vivo and in vitro alloreactivity assays reflect the same recognition process. (b) Four different RT1-controlled NK allospecificities (represented by the u, l, a, and n haplotypes) could be discerned when we used polyclonal NK cells from the PVG (RT1c) strain as effector cells. Three of the target specificities recognized were controlled mainly by the RT1.C region. (c) The expression of RT1.C region-controlled parental strain NK allodeterminants could be demonstrated in F1 hybrids heterozygous for the C region alone and were therefore inherited nonrecessively. (d) Loss of an RT1.C region-controlled NK allospecificity could be shown with the MHC mutant LEW.1LM1 rat strain characterized by a genomic deletion of about 100 kb of the C region. Taken together, these observations have demonstrated a major importance of the nonclassical class I region, i.e., RT1.C, in controlling rat NK allorecognition, and have thereby assigned a hitherto undescribed immunological property to this region. Furthermore, some of the present data are consistent with the existence of polymorphic NK-triggering alloantigens that are coded for by the RT1.C region.

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