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1.
Recent studies have shown that MHC class I molecules play an important role in the protective immune response to Mycobacterium tuberculosis infection. Here we showed that mice deficient in MHC class Ia, but possessing MHC class Ib (K(b-/-)D(b-/-) mice), were more susceptible to aerosol infection with M. tuberculosis than control mice, but less susceptible than mice that lack both MHC class Ia and Ib (beta(2)m(-/-) mice). The susceptibility of K(b-/-)D(b-/-) mice cannot be explained by the failure of CD8(+) T cells (presumably MHC class Ib-restricted) to respond to the infection. Although CD8(+) T cells were a relatively small population in uninfected K(b-/-)D(b-/-) mice, most already expressed an activated phenotype. During infection, a large percentage of these cells further changed their cell surface phenotype, accumulated in the lungs at the site of infection, and were capable of rapidly producing IFN-gamma following TCR stimulation. Histopathologic analysis showed widespread inflammation in the lungs of K(b-/-)D(b-/-) mice, with a paucity of lymphocytic aggregates within poorly organized areas of granulomatous inflammation. A similar pattern of granuloma formation has previously been observed in other types of MHC class I-deficient mice, but not CD8alpha(-/-) mice. Thus, neither the presence of MHC class Ib molecules themselves, nor the activity of a population of nonclassical CD8(+) effector cells, fully restored the deficit caused by the absence of MHC class Ia molecules, suggesting a unique role for MHC class Ia molecules in protective immunity against M. tuberculosis. 相似文献
2.
Vaccination with the T cell antigen Mtb 8.4 protects against challenge with Mycobacterium tuberculosis 总被引:18,自引:0,他引:18
Coler RN Campos-Neto A Ovendale P Day FH Fling SP Zhu L Serbina N Flynn JL Reed SG Alderson MR 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(10):6227-6235
The development of an effective vaccine against Mycobacterium tuberculosis is a research area of intense interest. Mounting evidence suggests that protective immunity to M. tuberculosis relies on both MHC class II-restricted CD4(+) T cells and MHC class I-restricted CD8(+) T cells. By purifying polypeptides present in the culture filtrate of M. tuberculosis and evaluating these molecules for their ability to stimulate PBMC from purified protein derivative-positive healthy individuals, we previously identified a low-m.w. immunoreactive T cell Ag, Mtb 8.4, which elicited strong Th1 T cell responses in healthy purified protein derivative-positive human PBMC and in mice immunized with recombinant Mtb 8.4. Herein we report that Mtb 8.4-specific T cells can be detected in mice immunized with the current live attenuated vaccine, Mycobacterium bovis-bacillus Calmette-Guérin as well as in mice infected i.v. with M. tuberculosis. More importantly, immunization of mice with either plasmid DNA encoding Mtb 8.4 or Mtb 8.4 recombinant protein formulated with IFA elicited strong CD4(+) T cell and CD8(+) CTL responses and induced protection on challenge with virulent M. tuberculosis. Thus, these results suggest that Mtb 8.4 is a potential candidate for inclusion in a subunit vaccine against TB. 相似文献
3.
Renukaradhya J. Gourapura Masood A. Khan Richard M. Gallo Daniel Shaji Jianyun Liu Randy R. Brutkiewicz 《PloS one》2013,8(8)
CD1d molecules are structurally similar to MHC class I, but present lipid antigens as opposed to peptides. Here, we show that MHC class I molecules physically associate with (and regulate the functional expression of) mouse CD1d on the surface of cells. Low pH (3.0) acid stripping of MHC class I molecules resulted in increased surface expression of murine CD1d on antigen presenting cells as well as augmented CD1d-mediated antigen presentation to NKT cells. Consistent with the above results, TAP1-/- mice were found to have a higher percentage of type I NKT cells as compared to wild type mice. Moreover, bone marrow-derived dendritic cells from TAP1-/- mice showed increased antigen presentation by CD1d compared to wild type mice. Together, these results suggest that MHC class I molecules can regulate NKT cell function, in part, by masking CD1d. 相似文献
4.
Mice deficient in CD4 T cells have only transiently diminished levels of IFN-gamma, yet succumb to tuberculosis 总被引:13,自引:0,他引:13
Caruso AM Serbina N Klein E Triebold K Bloom BR Flynn JL 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(9):5407-5416
CD4 T cells are important in the protective immune response against tuberculosis. Two mouse models deficient in CD4 T cells were used to examine the mechanism by which these cells participate in protection against Mycobacterium tuberculosis challenge. Transgenic mice deficient in either MHC class II or CD4 molecules demonstrated increased susceptibility to M. tuberculosis, compared with wild-type mice. MHC class II-/- mice were more susceptible than CD4-/- mice, as measured by survival following M. tuberculosis challenge, but the relative resistance of CD4-/- mice did not appear to be due to increased numbers of CD4-8- (double-negative) T cells. Analysis of in vivo IFN-gamma production in the lungs of infected mice revealed that both mutant mouse strains were only transiently impaired in their ability to produce IFN-gamma following infection. At 2 wk postinfection, IFN-gamma production, assessed by RT-PCR and intracellular cytokine staining, in the mutant mice was reduced by >50% compared with that in wild-type mice. However, by 4 wk postinfection, both mutant and wild-type mice had similar levels of IFN-gamma mRNA and protein production. In CD4 T cell-deficient mice, IFN-gamma production was due to CD8 T cells. Thus, the importance of IFN-gamma production by CD4 T cells appears to be early in infection, lending support to the hypothesis that early events in M. tuberculosis infection are crucial determinants of the course of infection. 相似文献
5.
Doi T Yamada H Yajima T Wajjwalku W Hara T Yoshikai Y 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(6):3806-3813
One of the oligopolymorphic MHC class Ib molecules, H2-M3, presents N-formylated peptides derived from bacteria. In this study, we tested the ability of an H2-M3-binding peptide, TB2, to induce protection in C57BL/6 mice against Mycobacterium tuberculosis. Immunization with bone marrow-derived dendritic cell (BMDC) pulsed with TB2 or a MHC class Ia-binding peptide, MPT64(190-198) elicited an expansion of Ag-specific CD8+ T cells in the spleen and the lung. The number of TB2-specific CD8+ T cells reached a peak on day 6, contracted with kinetics similar to MPT64(190-198)-specific CD8+ T cells and was maintained at an appreciable level for at least 60 days. The TB2-specific CD8+ T cells produced less effector cytokines but have stronger cytotoxic activity than MPT64(190-198)-specific CD8+ T cells. Mice immunized with TB2-pulsed BMDC as well as those with MPT64(190-198)-pulsed BMDC showed significant protection against an intratracheal challenge with M. tuberculosis H37Rv. However, histopathology of the lung in mice immunized with TB2-pulsed BMDC was different from mice immunized with MPT64(190-198)-pulsed BMDC. Our results suggest that immunization with BMDC pulsed with MHC class Ib-restricted peptides would be a useful vaccination strategy against M. tuberculosis. 相似文献
6.
Chen L Jay DC Fairbanks JD He X Jensen PE 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(12):6463-6472
Conventional MHC class Ia-restricted CD8(+) T cells play a dominant role in the host response to virus infections, but recent studies indicate that T cells with specificity for nonclassical MHC class Ib molecules may also participate in host defense. To investigate the potential role of class Ib molecules in anti-viral immune responses, K(b-/-)D(b-/-)CIITA(-/-) mice lacking expression of MHC class Ia and class II molecules were infected with lymphocytic choriomeningitis virus (LCMV). These animals have a large class Ib-selected CD8(+) T cell population and they were observed to mediate partial (but incomplete) virus clearance during acute LCMV infection as compared with K(b-/-)D(b-/-)β(2)-microglobulin(-/-) mice that lack expression of both MHC class Ia and class Ib molecules. Infection was associated with expansion of splenic CD8(+) T cells and induction of granzyme B and IFN-γ effector molecules in CD8(+) T cells. Partial virus clearance was dependent on CD8(+) cells. In vitro T cell restimulation assays demonstrated induction of a population of β(2)-microglobulin-dependent, MHC class Ib-restricted CD8(+) T cells with specificity for viral Ags and yet to be defined nonclassical MHC molecules. MHC class Ib-restricted CD8(+) T cell responses were also observed after infection of K(b-/-)D(b-/-)mice despite the low number of CD8(+) T cells in these animals. Long-term infection studies demonstrated chronic infection and gradual depletion of CD8(+) T cells in K(b-/-)D(b-/-)CIITA(-/-) mice, demonstrating that class Ia molecules are required for viral clearance. These findings demonstrate that class Ib-restricted CD8(+) T cells have the potential to participate in the host immune response to LCMV. 相似文献
7.
G Szalay C H Ladel C Blum L Brossay M Kronenberg S H Kaufmann 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(12):6955-6958
Protection against intracellular bacteria by T cells is regulated by Ag-presenting molecules, which comprise classical MHC class I molecules, MHC class II molecules, and nonclassical MHC class Ib molecules. The role of CD1 molecules, which are structurally similar to classical MHC class I gene products, but less polymorphic, is not understood so far. We show that CD1 surface expression increased on APC in Listeria-infected mice. The in vivo treatment with anti-CD1 mAb reduced TGF-beta 2 levels and concomitantly increased secretion of the proinflammatory cytokine TNF, the Th1 cell promoting cytokine IL-12, and the Th1 cell cytokine IFN-gamma at the onset of listerial infection. These findings point to a regulatory role of CD1-reactive cells in the immune response against listeriosis. 相似文献
8.
M Shirai C D Pendleton J A Berzofsky 《Journal of immunology (Baltimore, Md. : 1950)》1992,148(6):1657-1667
A few cases have been described of antigenic determinants that are broadly presented by multiple class II MHC molecules, especially murine I-E or human DR, in which polymorphism is limited to the beta chain, and the alpha chain is conserved. However, no similar cases have been studied for presentation by class I MHC molecules. Because both domains of the MHC peptide binding site are polymorphic in class I molecules, exploring permissiveness in class I presentation would be of interest, and also such broadly presented antigenic determinants would clearly be useful for vaccine development. We had defined an immunodominant determinant, P18, of the HIV-1 gp160 envelope protein recognized by human and murine CTL. To determine the range of class I MHC molecules that could present this peptide and to determine whether two HIV-1 gp160 Th cell determinants, T1 and HP53, could also be presented by class I MHC molecules, we attempted to generate CTL specific for these three peptides in 10 strains of B10 congenic mice, representing 10 MHC types, and BALB/c mice. P18 was presented by at least four different class I MHC molecules from independent haplotypes (H-2d, p, u, and q to CD8+ CTL. In H-2d and H-2q the presentation was mapped to the D-end class I molecule, and for Dd, a requirement for both the alpha 1 and alpha 2 domains of Dd, not Ld, was found. HP53 was also presented by the same four different class I MHC molecules to CD8+ CTL although at higher concentrations. T1 was presented by class I molecules in three different strains of distinct MHC types (B10.M, H-2f; B10.A, H-2a; and B10, H-2b) to CTL. The CTL specific for P18 and HP53 were shown to be CD8+ and CD4- and to kill targets expressing endogenously synthesized whole gp160 as well as targets pulsed with the corresponding peptide. To compare the site within each peptide presented by the different class I molecules, we used overlapping and substituted peptides and found that the critical regions of each peptide are the similar for all four MHC molecules. Thus, antigenic sites are broadly or permissively presented by class I MHC molecules even without a nonpolymorphic domain as found in DR and I-E, and these sequences may be of broad usefulness in a synthetic vaccine. 相似文献
9.
Serreze DV Holl TM Marron MP Graser RT Johnson EA Choisy-Rossi C Slattery RM Lieberman SM DiLorenzo TP 《Journal of immunology (Baltimore, Md. : 1950)》2004,172(2):871-879
Development of autoreactive CD4 T cells contributing to type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is either promoted or dominantly inhibited by particular MHC class II variants. In addition, it is now clear that when co-expressed with other susceptibility genes, some common MHC class I variants aberrantly mediate autoreactive CD8 T cell responses also essential to T1D development. However, it was unknown whether the development of diabetogenic CD8 T cells could also be dominantly inhibited by particular MHC variants. We addressed this issue by crossing NOD mice transgenically expressing the TCR from the diabetogenic CD8 T cell clone AI4 with NOD stocks congenic for MHC haplotypes that dominantly inhibit T1D. High numbers of functional AI4 T cells only developed in controls homozygously expressing NOD-derived H2(g7) molecules. In contrast, heterozygous expression of some MHC haplotypes conferring T1D resistance anergized AI4 T cells through decreased TCR (H2(b)) or CD8 expression (H2(q)). Most interestingly, while AI4 T cells exert a class I-restricted effector function, H2(nb1) MHC class II molecules can contribute to their negative selection. These findings provide insights to how particular MHC class I and class II variants interactively regulate the development of diabetogenic T cells and the TCR promiscuity of such autoreactive effectors. 相似文献
10.
Kobrynski LJ Sousa AO Nahmias AJ Lee FK 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(4):1787-1790
T cell involvement in Ab responses to thymus-independent type 2 Ags is an immunologic enigma. The identity of these cells and the mechanisms of their TCR engagement to carbohydrate molecules remain unknown. We measured IgG Ab production after immunization with pneumococcal polysaccharides in mice with disruptions in selected genes of the T cell pathway. Nonclassical MHC class I-like CD1 molecules and MHC class I-dependent CD8+ cells were found to be essential. Our findings set forth a new paradigm for humoral responses in which CD1 expression as well as a subset of CD8+ cells are required to provide helper function for Ab production against thymus-independent type 2 polysaccharides, similar to MHC class II-restricted CD4+ cells for protein Ags. 相似文献
11.
Debbabi H Ghosh S Kamath AB Alt J Demello DE Dunsmore S Behar SM 《American journal of physiology. Lung cellular and molecular physiology》2005,289(2):L274-L279
Type II alveolar epithelial cells (AEC) can produce various antimicrobial and proinflammatory effector molecules. This, together with their abundance and strategic location, suggests a role in host defense against pulmonary pathogens. We report that murine type II AEC, like their human counterparts, express class II major histocompatibility complex (MHC). Using a murine model of pulmonary tuberculosis, we find that type II AEC become activated and have increased cell surface expression of class II MHC, CD54, and CD95 following infection. Type II AEC use the class II MHC pathway to process and present mycobacterial antigens to immune CD4+ T cells isolated from mice infected with Mycobacterium tuberculosis. Therefore, not only can type II AEC contribute to the pulmonary immunity by secreting chemokines that recruit inflammatory cells to the lung, but they can also serve as antigen-presenting cells. Although type II AEC are unlikely to prime na?ve T cells, their ability to present antigens to T cells demonstrates that they can participate in the effector phase of the immune response. This represents a novel role for type II AEC in the immunological response to pulmonary pathogens. 相似文献
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13.
Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells 总被引:21,自引:0,他引:21
Gabrilovich DI Velders MP Sotomayor EM Kast WM 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(9):5398-5406
The mechanism of tumor-associated T cell dysfunction remains an unresolved problem of tumor immunology. Development of T cell defects in tumor-bearing hosts are often associated with increased production of immature myeloid cells. In tumor-bearing mice, these immature myeloid cells are represented by a population of Gr-1(+) cells. In this study we investigated an effect of these cells on T cell function. Gr-1(+) cells were isolated from MethA sarcoma or C3 tumor-bearing mice using cell sorting. These Gr-1(+) cells expressed myeloid cell marker CD11b and MHC class I molecules, but they lacked expression of MHC class II molecules. Tumor-induced Gr-1(+) cells did not affect T cell responses to Con A and to a peptide presented by MHC class II. In sharp contrast, Gr-1(+) cells completely blocked T cell response to a peptide presented by MHC class I in vitro and in vivo. Block of the specific MHC class I molecules on the surface of Gr-1(+) cells completely abrogated the observed effects of these cells. Thus, immature myeloid cells specifically inhibited CD8-mediated Ag-specific T cell response, but not CD4-mediated T cell response. Differentiation of Gr-1(+) cells in the presence of growth factors and all-trans retinoic acid completely eliminated inhibitory potential of these cells. This may suggest a new approach to cancer treatment. 相似文献
14.
Beta 2-microglobulin-deficient background ameliorates lethal phenotype of the TGF-beta 1 null mouse.
S Kobayashi K Yoshida J M Ward J J Letterio G Longenecker L Yaswen B Mittleman E Mozes A B Roberts S Karlsson A B Kulkarni 《Journal of immunology (Baltimore, Md. : 1950)》1999,163(7):4013-4019
TGF-beta 1 null (TGF-beta1-/-) mice die at 3-4 wk of age and show an autoimmune inflammatory phenotype associated with enhanced expression of both class I and II MHC molecules. To determine the role of MHC class I Ags in the autoimmune manifestations and the inflammation observed in TGF-beta 1-/- mice, we generated TGF-beta 1-/- mice in the genetic background of beta 2-microglobulin deficiency (beta 2M-/-). TGF-beta 1-/-;beta 2M-/- mice had improved survival compared with TGF-beta 1-/- mice. Histopathological examination showed less severe inflammation, especially in the heart, where Mac-2 reactive macrophages were significantly decreased as compared with TGF-beta 1-/- mice. In vivo depletion of CD8+ T cells in TGF-beta 1-/- mice confirmed suppression of inflammation and reduction in the severity of the wasting syndrome. MHC class II mRNA expression in TGF-beta 1-/-;beta 2M-/- mice was also lower than that in TGF-beta 1-/- mice, suggesting reduced systemic inflammation. Autoimmune response as judged by serum Ab titers to ssDNA and 16/6 Id and by immune complex deposits in kidney was reduced in TGF-beta 1-/-;beta 2M-/- mice, when compared with that in TGF-beta 1-/- mice. Our data thus indicate that MHC class I molecules influence the development of the autoimmunity and the inflammation seen in TGF-beta 1-/- mice and CD8+ T cells may have a contribution to the inflammation in TGF-beta 1-/- mice. 相似文献
15.
Regulation of homeostasis in the immune system includes mechanisms that promote survival of resting T lymphocytes, and others that control activation-induced cell death (AICD). In this study, we report on the use of a transgenic mouse model to test the role of CD4-MHC class II interactions for the susceptibility of CD4+ T lymphocytes to AICD, and for the survival of resting CD4+ T cells in peripheral lymphoid organs. The only I-Abeta gene expressed in these mice is an Abetak transgene with a mutation that prevents MHC class II molecules from interacting with CD4. We show increased apoptosis in CD4+ T lymphocytes derived from wild-type, but not from mutant Abetak transgenic mice following stimulation with staphylococcal enterotoxin A. Therefore, AICD may be impaired in CD4+ T cells derived from mutant Abetak transgenic mice. Importantly, we observed much higher apoptosis in resting CD4+ T cells from mutant Abetak transgenic mice than from wild-type mice. Furthermore, resting CD4+ T cells from mutant Abetak transgenic mice expressed higher levels of cell surface CD95 (Fas, APO-1). Ab-mediated cross-linking of CD95 further increased apoptosis in CD4+ T cells from mutant Abetak transgenic mice, but not from wild-type mice, suggesting apoptosis involved CD95 signaling. When cocultured with APC-expressing wild-type MHC class II molecules, apoptosis in resting CD4+ T lymphocytes from mutant Abetak transgenic mice was reduced. Our results show for the first time that interactions between CD4 and MHC class II molecules are required for the survival of resting CD4+ T cells in peripheral lymphoid organs. 相似文献
16.
Cutting edge: a single MHC class Ia is sufficient for CD8 memory T cell differentiation 总被引:1,自引:0,他引:1
Recent studies have suggested a role for MHC class Ib molecules in providing signals for memory T cell differentiation during the early phases of acute infection. To test this hypothesis, we assessed the development of effector and memory CD8 T cells in transgenic mice expressing a single chain H-2D(d)/beta2-microglobulin (beta2M) fusion protein on a beta2M-deficient background. These mice thus express a single MHC class Ia in the absence of all other beta2M-dependent class Ia and Ib molecules. Following infection with a recombinant vaccinia virus expressing a known D(d)-restricted epitope from HIV-1 gp160, the development of effector and memory cells CD8 T cells was comparable to control mice. Furthermore, these memory cells responded rapidly and robustly to antigenic restimulation. Therefore, we conclude that full CD8 memory differentiation requires only a single MHC class Ia chain, ruling out a requirement for MHC class Ib molecules in this process. 相似文献
17.
CD1 molecules are MHC class I-like glycoproteins whose expression is essential for the development of a unique subset of T cells, the NK T cells. To evaluate to what extent CD1 contributes to the development of CD4+ and CD8+ T cells, we generated CD1oIIo and CD1oTAPo mice and compared the generation of T cells in these double-mutant mice and IIo or TAPo mice. FACS analysis showed that the number of CD4+ T cells in CD1oIIo mice was reduced significantly compared with the corresponding population in IIo mice. Both CD4+ NK1.1+ and the CD4+ NK1.1- population were reduced in CD1oIIo mice, suggesting that CD1 can select not only CD4+ NK1.1+ T cells but also some NK1.1- CD4+ T cells. Functional analysis showed that the residual CD4+ cells in CD1oIIo can secrete large amounts of IFN-gamma and a significant amount of IL-4 during primary stimulation with anti-CD3, suggesting that this population may be enriched for NK T cells restricted by other class I molecules. In contrast to the CD4+ population, no significant differences in the CD8+ T cell compartment can be detected between TAPo and CD1oTAPo mice in all lymphoid tissues tested, including intestinal intraepithelial lymphocytes. Our data suggest that, unlike other MHC class I molecules, CD1 does not contribute in a major way to the development of CD8+ T cells. 相似文献
18.
Recipient MHC class II expression is required to achieve long-term survival of murine cardiac allografts after costimulatory blockade. 总被引:14,自引:0,他引:14
A Yamada A Chandraker T M Laufer A J Gerth M H Sayegh H Auchincloss 《Journal of immunology (Baltimore, Md. : 1950)》2001,167(10):5522-5526
To study the role of the direct and indirect pathways in achieving tolerance, we used genetically altered mouse strains in two ways: 1) MHC class II-deficient mice were used as donors of skin and cardiac grafts to eliminate the direct CD4(+) T cell response, and 2) B6 II(-)4(+) mice, which are MHC class II-deficient mice expressing an MHC class II transgene only on thymic epithelium, were used as recipients of normal grafts. These mice cannot mount an indirect response. Eliminating the indirect pathway actually made it more difficult to achieve prolonged allograft survival when we used costimulatory blockade than when both pathways were available. Costimulatory blockade was ineffective even when CD4(+) T cells from normal animals were transferred into recipients that lacked MHC class II molecules. These results suggest that an active CD4(+) response through the indirect pathway is necessary for costimulatory blockade to be effective in prolonging allograft survival. 相似文献
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20.
Molano A Park SH Chiu YH Nosseir S Bendelac A Tsuji M 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(10):5005-5009
Biochemical analysis has suggested that self GPI anchors are the main natural ligand associated with mouse CD1d molecules. A recent study reported that Valpha14+ NK T cells responded to self as well as foreign (parasite-derived) GPIs in a CD1d-dependent manner. It further reported that the IgG response to the Plasmodium berghei malarial circumsporozoite (CS) protein was severely impaired in CD1d-deficient mice, leading to a model whereby NK T cells, upon recognition of CD1d molecules presenting the CS-derived GPI anchor, provide help for B cells secreting anti-CS Abs. We tested this model by comparing the anti-CS Ab responses of wild-type, CD1d-deficient, and MHC class II-deficient mice. We found that the IgG response to the CS protein was solely MHC class II-dependent. Furthermore, by measuring the response of a broad panel of CD1d-autoreactive T cells to GPI-deficient CD1d-expressing cells, we found that GPIs were not required for autoreactive responses. 相似文献