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1.
Mayumi Nakagawa Richard A. Zeff Steven S. Geier Jeffrey A. Bluestone Stanley G. Nathenson 《Immunogenetics》1986,24(6):381-385
A cell-surface-associated variant H-2K product was expressed by an Abelson virus-induced pre-B-cell line after chemical mutagenesis with ethyl methane sulfonate. The variant cell line (R8.313) was previously demonstrated to have altered allodeterminants in Kb as demonstrated by both Kb-specific monoclonal antibody binding and alloreactive cytotoxic T lymphocyte (CTL) cytolysis. The mutant H-2K
b gene from R8.313 was cloned and characterized in detail. DNA sequence analysis of the region of the gene corresponding to the three extracellular domains identified a single point mutation resulting in a leucine-to-phenylalanine substitution at amino acid residue 82. The site of mutation within the 1 domain was confirmed by oligonucleotide hybridization analysis. Mouse L-cell fibroblasts transfected with the mutant gene were recognized with the same monoclonal antibody binding and CTL lytic pattern as the R8.313 cell line, confirming that the altered phenotype of the mutant cell line was due to a point mutation in the H-2K
b gene. These data further extend the hypothesis that the region of amino acid residues 70–90 in the 1 domain is important in the formation of both antibody and CTL-defined recognition structures on major histocompatibility complex class I molecules. 相似文献
2.
We previously described the generation and specificity of H-2-restricted cytolytic lymphocytes (CTL) directed against tumors induced by AKR/Gross murine leukemia viruses (MuLV). Such anti-AKR/Gross virus CTL demonstrated type specificity; only tumors induced by endogenous MuLV that expressed the Gross cell-surface antigen were lysed. These CTL and their precursor also recognized normal spleen cells from AKR-H-2
b
, but not AKR-H-2
b
, Fv-1
b
mice, however, suggesting that N-ecotropic, retrovirus-associated antigens were primarily involved. Here, expression of these CTL-defined retroviral antigens by H-2b-positive AKR × C57L recombinant inbred strains was examined by using normal spleen cells as stimulators in the generation of specific anti-AKR/Gross virus CTL. Analysis of the strain distribution pattern of stimulation indicated that a single proviral locus, Akv-1, was primarily, if not entirely, responsible for CTL-defined retroviral antigen expression. The lack of correlation with two other well-defined proviral loci was interesting. Whereas Akv-3 is known to encode a defective virus, Akv-4 has been shown to code for an infectious virus thought to be very similar or identical to that of Akv-1. Although quantitative differences cannot be formally excluded, dose response experiments argued against this possibility and suggested that Akv-1 and Akv-4 may exhibit qualitative differences germane to antiviral CTL recognition. 相似文献
3.
The differential expression of H-2 specificities recognized by antibody and by cytotoxic T lymphocytes (CTL) has been studied using a clone (FY7) of the C57BL/6 leukemia cell line FBL-3 (H-2
b
/H-2
b
). Unlike C57BL/10 spleen cells, EL-4 lymphoma cells and Y57-2C leukemia cells (allH-2
b
/H-2
b
), FY7 failed to induce the primary in vitro generation of anti-H-2b CTL by (B10.A x A)F1 (H-2
a
/H-2
a
or (B10.D2 x BALB/c)F1 (H-2
d
/H-2
d
) responder spleen cells. In addition, FY7 was not lysed by, and did not competitively inhibit anti-H-2b CTL. Quantitative absorption tests with H-2Kb and H-2Db antisera revealed that FY7 expressed these antigens in quantitatively similar amounts to EL-4. The H-2Kb product of FY7 appeared to be identical with that of C57BL/10 spleen cells both in apparent molecular weight and isoelectric point. Yet FY7 failed to inhibit anti-H-2Kb CTL competitively in a cold target inhibition assay. Possible mechanisms are discussed for the lack of T-lymphocyte recognition of the H-2Kb-gene product expressed by FY7.Abbreviations used in this paper CTL
cytotoxic T lymphocytes
- MHC
major histocompatibility complex
- MLC
mixed lymphocyte culture
- PAGE
polyacrylamide gel electrophoresis 相似文献
4.
Françoise Albert Michel Buferne Claude Boyer Anne-Marie SchmittVerhulst 《Immunogenetics》1982,16(6):533-549
To study the interactions between T cells and class I MHC products, we developed in vitro a T-cell line reactive to H-2Kb stimulating cells and derived T-cell clones from it. Although the T-cell line could proliferate in the absence of exogeneous T-cell growth factors when stimulated with H-2Kb spleen cells, each of the derived T-cell clones required both H-2Kb stimulating cells and an external source of T-cell growth factor for its propagation. Each of the T-cell clones was also cytolysic for H-2Kb target cells. Such T-cell clones allowed the comparison of the antigenic requirements for proliferation and cytolysis. By using H-2K
b
mutant mice, we found that while the original anti-H-2Kb T-cell line reacted with each of the six mutants tested, the individual T-cell clones could be distinguished in terms of their reactivity pattern. Similar fine specificity patterns were found when H-2K
b
mutant cells were used as stimulating or target cells for any given T-cell clone. Each of the three monoclonal H-2Kb-specific antibodies reacting with different epitopes of the H-2Kb molecule totally inhibited H-2Kb-induced proliferation and lysis by the T-cell clones. Further blocking studies involved use of Fab antibody fragments and definition of their reactivity on cells from the H-2K
b
mutants. We concluded that: (1) blocking with a monoclonal antibody does not prove identity of alloantigens recognized by the T-cells and the antibody; (2) a monoclonal antibody could either block or not block H-2Kb-CTL interactions depending on structural variations of the H-2Kb molecule not affecting the CTL-H-2Kb functional interaction; (3) blocking one type of H-2Kb-T-cell interaction (induction of proliferation) always affects the other type (cytolysis).Abbreviations used in this paper MHC
major histocompatibility complex
- CTL
cytotoxic
- T
lymphocytes
- Th
T helper cells
- PMA
4-phorbol 12-myristate 13-acetate
- Con A
Concanavalin A
- LPS
E. coli lipopolysaccharide
- SCA
Con A stimulated rat spleen-cells supernatant
- SBD
B6 anti-DBA/2 mixed lymphocyte culture supernatant
- TCGF
T-cell growth factors
- IL-2
interleukin 2
- mAb
monoclonal antibody
- FCS
fetal calf serum
- PBS
phosphate buffered saline
- C
complement 相似文献
5.
Robert N. Jenkins Carla J. Aldrich Nicholas F. Landolfi Robert R. Rich 《Immunogenetics》1985,21(3):215-225
Cytotoxic T lymphocytes (CTL) activated in H-2 identical, Qa-1 disparate mixed leukocyte cultures recognize H-2-nonrestricted target antigens indistinguishable by strain or tissue distribution from serologically defined Qa-1 antigens. Cloned Qa-l-specific CTL define determinants encoded by four Qa-1 genotypes; we used anti-Qa-1 sera in antibody blocking experiments to determine if these determinants reside on molecules recognized by Qa-1-specific antibodies. Antisera containing Qa-1.1-specific and TL-specific antibodies blocked recognition of two CTL-defined determinants associated with Qa-1
a
. Although both Qa-1 and TL molecules are expressed on activated T cells from appropriate strains, our studies indicated that the CTL recognized Qa-1, not TL. In addition, anti-Qa-1.2 serum inhibited CTL recognition of Qa-1b- and Qa-1c-encoded determinants. Qa-1
d
target cells are unique in that they express determinants recognized by anti-Qa-1a CTL and by anti-Qa-1b CTL. Killing of Qa-1
d
targets by anti-Qa-1a CTL was not inhibited by anti-Qa-1.1 serum, but was partially inhibited by anti-Qa-1.2 serum. Cytotoxicity of Qa-1
d
cells by one anti-Qa-1b CTL clone was inhibited by both anti-Qa-1.2 and anti-Qa-1.1 sera, indicating close association of both serological determinants with the determinants recognized by the CTL. Thus, all of the CTL-defined Qa-1 determinants resided on molecules recognized by Qa-1-specific antibodies, but anti-Qa-1a CTL and Qa-1.1-specific antibodies did not have identical specificities.Abbreviations used in this paper B6
C57BL/6J
- CAB
concanavalin A stimulated lymphoblasts
- CML
cell-mediated lympholysis
- CTL
cytotoxic T lymphocyte
- NMS
normal mouse serum
- MHC
major histocompatibility complex
- MLC
mixed leukocyte culture
- MR
maximum release
- SMDM
supplemented Mishell-Dutton medium
- SR
spontaneous release 相似文献
6.
The interaction between class I major histocompatibility complex (MHC) products and T cells was studied using H-2Kb-specific alloreactive T-cell lines and clones obtained by repeated in vitro stimulation with allogeneic cells. Induction of proliferation of these T cells appeared to involve two signals: the H-2Kb alloantigen and interleukins. Immunopurified liposome-inserted H-2Kb, which stimulates specific secondary in vitro cytotoxic T lymphocyte (CTL) responses, could not replace cell-associated H-2Kb in the stimulation of these T-cell lines, even in the presence of feeder cells and interleukins. When T-cell lines were initiated in vitro and repeatedly stimulated with H-2Kb liposomes and feeder cells, it was possible to obtain T cells that could proliferate in response to H-2Kb liposomes in the presence of feeder cells and interleukin-2-containing supernatants or on H-2K
b
-expressing cells. Only stimulation with cells permitted maintenance of these T cells in culture for more than 12 weeks. Analyses of cell surface markers and of patterns of inhibition of proliferation by monoclonal antibodies (mAb) of T-cell lines induced in vitro with cell- or liposome-associated H-2Kb indicated that T-cell stimulation by class I antigen can occur in at least two ways. In the first, the H-2Kb-induced proliferation of Lyt-1- Lyt-2+ T4- T cells is inhibited by H-2Kb- and by Lyt-2-specific mAb, but not by Ia or T4-specific mAb. In the second, both Lyt-2+ and T4+ T cells are involved and the H-2Kb-induced proliferation is inhibited by H-2Kb- and Lyt-2-specific mAb and by Ia- and T4-specific mAb.Abbreviations used in this paper Ab
antibody
- mAb
monoclonal antibody
- C
complement
- i.p.
intraperitoneally
- PBS
phosphate-buffered saline
- PBS-B-N
PBS containing bovine serum albumin and NaN3
- CTL
cytotoxic T lymphocyte
- Th
T helper cell
- MHC
major histocompatibility complex
- PMA
4-phorbol 12-myristate 13-acetate
- SCA
concanavalin A-stimulated rat spleen cell supernatant
- SC16
EL4 clone 16 supernatant
- IL-1
interleukin-1
- IL-2
interleukin-2 (T-cell growth factor)
- FCS
fetal calf serum
- H-2Kb-lip.
H-2Kb inserted in liposomes
- C. E.
cell equivalents 相似文献
7.
In preparation for functional analyses, a study of the binding of H-2Kb-specific monoclonal antibodies (mAb) to formaldehyde (FOR)-fixed H-2b spleen or tumor cells revealed that three of nine mAb tested had lost reactivity with the FOR-fixed cells, whereas the reactivity of the other mAb generally did not diminish. Comparison of the reactivity of these mAb on untreated H-2K
bm
mutant cells and on FOR-treated H-2Kb cells suggests that for three mAb the total loss of reactivity on the latter could be a consequence of the alteration by FOR of lysine 89, which is substituted by alanine in mutant bm3. H-2KPb-specific alloreactive polyclonal or monoclonal CTL, all of which had retained reactivity with bm3 target cells, had also retained reactivity with FOR-fixed H-2b cells as indicated by cold target inhibition studies. The H-2Kb-specific CTL were probably reactive with conformational determinants of H-2Kb, which are dependent on the integrity of both the 1 and the 2 domains of the H-2Kb molecule. Results are compatible with FOR treatment selectively affecting a serological determinant in the 1 domain without affecting conformational-type CTL determinants.Abbreviations used in this paper CTL
cytotoxic T lymphocyte
- FOR
formaldehyde
- PBS
phosphatebuffered saline
- FCS
fetal calf serum
- mAb
monoclonal antibody
- TNBS
trinitrobenzene sulfonate 相似文献
8.
We have investigated the effect of immune selection against a single gene product on a cultured mouse Friend leukemia cell line. The clonal cell line used is heterozygous at theH-2 complex and expresses theH-2 d andH-2 b haplotypes. The genes selected against were theH-2K locus alleles. Variants were obtained after a single-step selection using either antiH-2Kb or anti-H-2Kd serum. The phenotypes of the variants obtained showed an interesting asymmetry between the two haplotypes. Selection against theH 2K b allele resulted in the isolation of the two expected types of variant-those that had lost only H-2Kb and those that had lost both H-2Kb and the linked H-2Db. Selection against H-2Kd yielded, exclusively, variants that had lost both the selected antigen and the linked H-2Dd. None of the variants showed an alteration in expression of antigens intrans configuration. Karyotypic analyses of the variants revealed that all the cells had retained both copies of chromosome 17 present in the wild-type cells. The results suggest that the variants did not emerge through chromosome loss. 相似文献
9.
The purpose of this work was to study the genetic basis of histocompatibility antigens encoded by the mouse minor histocompatibility
(H) locusH-3. Both class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) and class II MHC-restricted
helper T cells (TH) specific for antigens encoded by genes within theH-3 locus were isolated and analyzed. Typing a number of mouse strains for expression of antigens recognized by these TH and
CTL suggested that there was a different strain distribution pattern of expression of the antigens recognized by TH compared
with those recognized by CTL. Separation of the genes whose products stimulate TH from those whose products stimulate CTL
was suggested by: (1) analysis of the strain B10.FS(92NX)/Grf that has undergone recombination within theH-3 region; (2) genetic segregation studies of (B10.UW-H-3
b/Sn×C57BL/10Sn)F2 mice; and (3) F1 complementation studies in which CTL specific for products of the TH-defined gene(s) could not be detected, even in the absence
of immune responses to products of the CTL-defined genes. Taken together, these data suggest that in addition to two genes
(B2m andCd-1) within theH-3 region whose products typically stimulate class I MHC-restricted CTL, there is at least one additional gene whose product
selectively stimulates class II MHC-restricted TH. This new gene is located telomeric from the CTL-defined genes and between
the lociwe andun on chromosome 2. These data demonstrate a novel degree of complexity of theH-3 “locus” and suggest selective presentation of minor H gene products in the context of class I or class II MHC proteins. 相似文献
10.
F1 complementation results indicate that a new gene, putatively controlling a minor histocompatibility antigen, is closely linked to the minor histocompatibility gene,H-3, in the fifth linkage group of chromosome 2 of the mouse. This gene controls a product that was capable of inducing as well as acting as a target for cytotoxic lymphocytes (CTL). The lytic activity of CTL developed in B10.LP-H-3b mice specific for the product of the new gene of B10 was restricted to target cells possessing H-2Db antigens. This contrasts to the H-2Kb-restricted activity of H-3.1 specific CTL. 相似文献
11.
Use of hybridoma-resistant variant cell lines to study H-2D
b/FMR-specific cytotoxic T cells 总被引:1,自引:0,他引:1
An H-2D
b b heterozygous tumor cell line and a variant subclone bearing a mutant gene product were used to analyze the H-2Db specificity of cytotoxic T lymphocytes (CTL) generated during a Moloney murine sarcoma virus (MSV) infection. When the mutant cells were used as targets for MSV-specific CTL, the amount of cell lysis, compared with that seen with the nonmutant parental cells, was drastically decreased. However, cells of the mutant clones remained susceptible to allogeneic CTL specific for the nonmutant H-2Db molecule. The mutant cells also did not differ from the parent cells in their level of viral antigen expression. Biochemically the parental and mutant molecules were similar but not identical. The data indicate that minor alterations of the H-2 antigens caused by somatic mutation may prevent virus-infected cells from being recognized as targets by CTL. 相似文献
12.
Moloney leukemia virus-specific cytotoxic T lymphocytes (CTL), generated by secondary in vitro stimulation of spleen cells with syngeneic virus-infected cells, frequently lysed not only syngeneic virus-infected cells, but also noninfected allogeneic target cells. This phenomenon was studied with B6(H-2 b ) responder cells and a series of H-2K b -mutant responder cells. Thus, B6 Moloney-specific CTL lysed noninfected K b -mutant cells, but not B6 cells, whereas K b -mutant Moloney-specific CTL lysed noninfected B6 cells and not noninfected cells of the same mutant. Cold-target-inhibition studies showed that the CTL reactions against different allogeneic cells were mediated by different subpopulations of virus-specific CTL: lysis of allogeneic target cells was fully inhibited only by the same allogeneic and by syngeneic virus-infected cells, but not by another allogeneic cell, also lysed by the same effector-cell population. Lysis of syngeneic virus-infected cells could not be inhibited by allogeneic target cells. These data imply that a minority of virus-specific CTL shows cross-reactivity with a given allogeneic target cell. It is concluded that limited amino acid substitutions in the Kb molecule alter the repertoire of Moloney virus-specific CTL, as reflected in alloreactive CTL populations, even though the virus-specific CTL response. of B6 and all K b mutants is mainly Db-restricted. Thus, the development of tolerance to self class-I major histocompatibility complex (MHC) molecules affects the repertoire of self-restricted cytotoxic T cells. 相似文献
13.
Identification of the Cloned Gene for the Murine Transplantation Antigen H-2Kb by Hybridization with Synthetic Oligonucleotides 总被引:2,自引:0,他引:2
Dan H. Schulze Larry R. Pease Yuichi Obata Stanley G. Nathenson Antonio A. Reyes Satoshi Ikuta R. Bruce Wallace 《Molecular and cellular biology》1983,3(4):750-755
The H-2Kb gene is a member of the large major histocompatibility complex class I gene family. Since many members of this family cross-hybridize with class I cDNA probes, the cloned H-2Kb gene was identified by hybridization with specific oligonucleotide probes. This clone was definitively shown to encode the H-2Kb polypeptide by partial DNA sequencing and by serological and tryptic peptide analyses of the expressed product. 相似文献
14.
Bruce E. Elliott Arthur Kimura Ammon B. Peck Zoltan A. Nagy Hans Wigzell 《Immunogenetics》1981,12(1):525-540
A highly selected alloreactive T-cell line was developed by repeated restimulation of B10.D2/n lymph-node cells with irradiated C57BL/10Sn (BIO) spleen cells in long-term MLC for up to 2 1/2 years. Continuous growth of the line requires restimulation every 2 to 4 weeks with fresh H-2b stimulator cells. The line proliferates strongly against H-2b but not againstH-2
d
,H-2
f
,H-2
q
,H-2
r
, orH-2
s
stimulators. Analysis of recombinant mouse strains showed that the proliferative response is directed against I-Ab but not Kb or Db determinants. During the growth period of the line, strong cross-reactivity with H-2p (B10.P) and weak cross-reactivity with H-2k strains (e.g., CBA/J and B10.BR) was observed. A clone with exquisite specificity for I-Ab, but with no cross-reactivity with H-2p or H-2k was isolated from the line; thus clonal heterogeneity of the line still exists despite the highly selective growth conditions. — The majority of T cells from the line or clone were shown to bind I-Ab but not Kb or Db determinants either spontaneously during restimulation with fresh B10 stimulator cells or via membrane vesicles expressing I-Ab determinants. No killing activity by the line in either specific or nonspecific cytolytic T-cell assays was observed nor was the T 145 glycoprotein, characteristic of killer T cells, detected.Abbreviations used in this paper B6
C57BL/6J
- B10
C57BL/10Sn
- Con A
Concanavalin A
- CTL
cytotoxic T lymphocyte
- FCS
fetal calf serum
- FDA
fluorescein diacetate
- FITC
fluorescein isothiocyanate
- Ia
I-region-associated antigens
- LPS
lipopolysaccharide fromE. coli
- Lyt
T-lymphocyte-defined antigen
- MLC
mixed leukocyte culture
- NP-40
nonidet P-40
- PAGE
pofyacrylamide gel electrophoresis
- PHA
phytohemagglutinin fromPhaseolus vulgaris
- PM
plasma membrane
- SDS
sodium dodecyl sulfate
- TCGF
T-cell growth factor(s)
- TdR
thymidine 相似文献
15.
Characterization of a novel IRF-1-deficient mutant cell line 总被引:1,自引:0,他引:1
16.
A mouse cDNA library derived from the EL4 cell line (b-haplotype) was screened with a probe containing a small part of the H-2Kb coding region. One of the clones isolated, pH203, encodes a protein whose deduced amino acid sequence is identical with the known sequence of H-2Db in 141 of 141 positions available for comparison. The clone, therefore, is believed to code for the H-2Db transplantation antigen. The cDNA insert of pH203 contains the coding region for residues 82 through the carboxy-terminus of H-2Db, and includes 476 nucleotides of the 3-untranslated sequence. Comparison between the H-2Db cDNA clone and a previously isolated H-2Kb cDNA clone shows homologies of 83% and 91% at the amino acid and nucleotide levels, respectively. Analysis of DNA sequences at the 3-coding and untranslated regions suggests that the mRNAs of H-2Kb and H-2Db are spliced differently at their 3-coding ends. 相似文献
17.
A monoclonal H-2d-specific antibody markedly inhibits target-cell lysis mediated by two influenza virus A/JAP/57-specific, H-2K
d
-restricted cloned CTL lines. Three other A/JAP/57-specific, H-2
d
-restricted CTL clones (two of which are also restricted to H-2K
d
in target-cell recognition) are only minimally inhibited by this monoclonal antibody. The inhibitory effect of the antibody is not due to selective binding to certain cloned CTL lines but rather is due to blocking of a determinant on the target cell. The monoclonal antibody produces partial inhibition of lysis mediated by a heterogeneous population of A/JAP/57-specific, H-2
d
-restricted CTL. Likewise the profound, selective inhibition of cytolysis produced by the H-2d-specific monoclonal antibody could not be reproduced with a conventional H-2d alloantiserum. These observations suggest that more than one site on a particular H-2K or H-2D molecule can serve as a determinant for H-2-restricted CTL recognition. They furthermore imply that there is more than one recognition structure (receptor) for self MHC products clonally distributed among a population of H-2-restricted CTL directed to a particular antigen. 相似文献
18.
Lymph-node cells fromH-2 allogeneic, intra-H-2 recombinant andH-2 mutant congenic strains were sensitized in limiting dilution cultures to quantitate the cytotoxic T-lymphocyte precursor frequencies (CTL.Pf) against antigens encoded by different regions of theH-2 complex. When fourH-2K
b
mutants of C57BL/6 (B6) were tested, we observed anti-B6 CTL.Pf that were as high or higher than those of recombinant strains which differ from B6 at theK end of theH-2 complex. Relative to strains completelyH–2 allogeneic to B6, the CTL.Pf inH-2
bm1,H-2
bm3 andH-2
bm5 averaged 40–50 percent, andH-2
bm8 averaged 140 percent. Recombinant strains B10.A (4R) and B10.D2 (R103), which differ from B6 at theK end of theH-2 complex, averaged 60 percent of the completelyH-2 allogeneic value. Since the mutant and wild-type gene products have no serological and minimal structural differences relative to other alleles atH-2K, these results indicate that the CTL.Pf does not increase with increasing H-2 antigenic disparity between any two strains. Rather, the data suggests that the T-cell receptor repertoire recognizes those H-2 molecules or determinants closest to self. 相似文献
19.
Tosiki Nisizawa Bruce M. Ewenstein Hiroshi Uehara Diane McGovern Stanley G. Nathenson 《Immunogenetics》1981,12(1):33-44
Biochemical analysis of the H-2K-gene product from the MHC mutant strainbml and from the C57BL/6 parent strain has been carried out in order to characterize the structural differences between parent and mutant K-gene products. Based on comparative tryptic peptide mapping of the cyanogen bromide fragments from these glycoproteins, two peptide differences were localized to the CN-Ia fragment. Partial amino-acid sequence analysis revealed two alterations in the primary structure of Kbml involving substitutions of tyrosine for arginine at position 155, and tyrosine for leucine at position 156. Both of these amino-acid replacements require a minimum of two nucleotide base changes at the nucleic acid level. These changes were the only alterations noted differentiating the Kbml and Kb glycoproteins. However, because our techniques allow us to analyze only 75 to 80 percent of the extra cellular portion of H-2Kb, it is possible there are other undetected changes. Nonetheless, the biochemical data are consistent with the hypothesis that the structural alterations noted in the Kbml mutant glycoprotein are directly related to the observed immunological specificity relative to the parent Kb molecule. Peptide comparisons of the Kb molecules of two C57BL/6 sublines and of the H-2b lymphoblastoid cell line, EL-4, disclosed no difference. 相似文献
20.
Kevin D. Pavelko Yanice Mendez-Fernandez Michael P. Bell Michael J. Hansen Aaron J. Johnson Chella S. David Moses Rodriguez Larry R. Pease 《PLoS pathogens》2012,8(2)
Structural diversity in the peptide binding sites of the redundant classical MHC antigen presenting molecules is strongly selected in humans and mice. Although the encoded antigen presenting molecules overlap in antigen presenting function, differences in polymorphism at the MHC I A, B and C loci in humans and higher primates indicate these loci are not functionally equivalent. The structural basis of these differences is not known. We hypothesize that classical class I loci differ in their ability to direct effective immunity against intracellular pathogens. Using a picornavirus infection model and chimeric H-2 transgenes, we examined locus specific functional determinants distinguishing the ability of class I sister genes to direct effective anti viral immunity. Whereas, parental FVB and transgenic FVB mice expressing the H-2Kb gene are highly susceptible to persisting Theiler''s virus infection within the CNS and subsequent demyelination, mice expressing the Db transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of Kb but encoding the peptide binding domain of Db, develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric Kbα1α2Db gene (low) and Db (high) in the CNS of infected mice mirror expression levels of their endogenous H-2q counterparts in FVB mice. These findings demonstrate that locus specific elements other than those specifying peptide binding and T cell receptor interaction can determine ability to clear virus infection. This finding provides a basis for understanding locus-specific differences in MHC polymorphism, characterized best in human populations. 相似文献