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1.
Donor APCs are required for maximal GVHD but not for GVL 总被引:23,自引:0,他引:23
Matte CC Liu J Cormier J Anderson BE Athanasiadis I Jain D McNiff J Shlomchik WD 《Nature medicine》2004,10(9):987-992
Graft-versus-host disease (GVHD) is a major source of morbidity in allogenic stem cell transplantation. We previously showed that recipient antigen-presenting cells (APCs) are required for CD8-dependent GVHD in a mouse model across only minor histocompatibility antigens (minor H antigens). However, these studies did not address the function of donor-derived APCs after GVHD is initiated. Here we show that GVHD develops in recipients of donor major histocompatibility complex class I-deficient (MHC I(-)) bone marrow. Thus, after initial priming, CD8 cells caused GVHD without a further requirement for hematopoietic APCs, indicating that host APCs are necessary and sufficient for GHVD. Nonetheless, GVHD was less severe in recipients of MHC I(-) bone marrow. Therefore, once initiated, GVHD is intensified by donor-derived cells, most probably donor APCs cross-priming alloreactive CD8 cells. Nevertheless, donor APCs were not required for CD8-mediated graft-versus-leukemia (GVL) against a mouse model of chronic-phase chronic myelogenous leukemia. These studies identify donor APCs as a new target for treating GVHD, which may preserve GVL. 相似文献
2.
Lee BO Moyron-Quiroz J Rangel-Moreno J Kusser KL Hartson L Sprague F Lund FE Randall TD 《Journal of immunology (Baltimore, Md. : 1950)》2003,171(11):5707-5717
CD40 is an important costimulatory molecule for B cells as well as dendritic cells, monocytes, and other APCs. The ligand for CD40, CD154, is expressed on activated T cells, NK cells, mast cells, basophils, and even activated B cells. Although both CD40(-/-) and CD154(-/-) mice have impaired ability to isotype switch, form germinal centers, make memory B cells, and produce Ab, it is not entirely clear whether these defects are intrinsic to B cells, to other APCs, or to T cells. Using bone marrow chimeric mice, we investigated whether CD40 or CD154 must be expressed on B cells for optimal B cell responses in vivo. We demonstrate that CD40 expression on B cells is required for the generation of germinal centers, isotype switching, and sustained Ab production, even when other APCs express CD40. In contrast, the expression of CD154 on B cells is not required for the generation of germinal centers, isotype switching, or sustained Ab production. In fact, B cell responses are completely normal when CD154 expression is limited exclusively to Ag-specific T cells. These results suggest that the interaction of CD154 expressed by activated CD4 T cells with CD40 expressed by B cells is the primary pathway necessary to achieve B cell activation and differentiation and that CD154 expression on B cells does not noticeably facilitate B cell activation and differentiation. 相似文献
3.
Rizzo LV Morawetz RA Miller-Rivero NE Choi R Wiggert B Chan CC Morse HC Nussenblatt RB Caspi RR 《Journal of immunology (Baltimore, Md. : 1950)》1999,162(5):2613-2622
Protection from the development of experimental autoimmune uveitis (EAU) can be induced by feeding mice interphotoreceptor retinoid binding protein before uveitogenic challenge with the same protein. Two different regimens are equally effective in inducing protective tolerance, although they seem to do so through different mechanisms: one involving regulatory cytokines (IL-4, IL-10, and TGF-beta), and the other with minimal involvement of cytokines. Here we studied the importance of IL-4 and IL-10 for the development of oral tolerance using mice genetically engineered to lack either one or both of these cytokines. In these animals we were able to protect against EAU only through the regimen inducing cytokine-independent tolerance. When these animals were fed a regimen that in the wild-type animal is thought to predominantly induce regulatory cells and is associated with cytokine secretion, they were not protected from EAU. Interestingly, both regimens were associated with reduced IL-2 production and proliferation in response to interphotoreceptor retinoid binding protein. These findings indicate that both IL-4 and IL-10 are required for induction of protective oral tolerance dependent on regulatory cytokines, and that one cytokine cannot substitute for the other in this process. These data also underscore the fact that oral tolerance, manifested as suppression of proliferation and IL-2 production, is not synonymous with protection from disease. 相似文献
4.
Kagami S Rizzo HL Kurtz SE Miller LS Blauvelt A 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(9):5453-5462
IL-23 and Th17 cells play important roles in host defense against systemic infections with extracellular bacteria and fungi, although their roles in immunity against localized skin infections are less well defined. Here, the contributions of IL-23 and Th17 cytokines in host defense against cutaneous Candida albicans infection were evaluated. Mice deficient in IL-23 or IL-17A demonstrated delayed healing and decreased IL-17A production after skin infection with C. albicans compared with wild-type mice or mice deficient in IL-12 or IL-22. Histologic examination revealed epidermal hyperplasia overlying infected dermis four days postinoculation in wild-type mice. In IL-23-deficient mice, fungal burden was greater in skin, neither IL-17A nor IL-22 mRNAs were expressed postinfection, and these mice demonstrated only minimal epidermal hyperplasia. Exogenous recombinant IL-17A injected at the site of skin infection promoted more rapid healing of candidiasis in both wild-type mice and mice deficient in IL-23 and IL-12. Taken together, these results demonstrate that IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal host defense against cutaneous candidiasis. In addition, recombinant IL-17A may serve as a potential therapy to enhance healing in individuals with chronic cutaneous candidiasis. 相似文献
5.
6.
The CD154/CD40 interaction required for retrovirus-induced murine immunodeficiency syndrome is not mediated by upregulation of the CD80/CD86 costimulatory molecules
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C57BL/6 (B6) mice infected with LP-BM5 retroviruses develop disease, including an immunodeficiency similar to AIDS. This disease, murine AIDS (MAIDS), is inhibited by in vivo anti-CD154 monoclonal antibody treatment. The similar levels of insusceptibility of CD40(-/-) and CD154(-/-) B6 mice indicate that CD154/CD40 molecular interactions are required for MAIDS. CD4(+) T and B cells, respectively, provide the CD154 and CD40 expression needed for MAIDS induction. Here, the required CD154/CD40 interaction is shown to be independent of CD80 and CD86 expression: CD80/CD86(-/-) B6 mice develop MAIDS after LP-BM5 infection. 相似文献
7.
Generation of protective immunity against an immunogenic carcinoma requires CD40/CD40L and B7/CD28 interactions but not CD4+ T cells 总被引:8,自引:0,他引:8
Interactions between CD40 and CD40L play a central role in the regulation of both humoral and cellular immunity. Recently, interactions between these molecules have also been implicated in the generation of protective cell-mediated tumor immunity. We have generated a tumor model in which a well-understood and clearly immunostimulatory antigen, influenza hemagglutinin has been transfected into the BALB/c-derived, MHC-class-I-positive, B7-deficient murine mammary carcinoma, MT901. In this model, expression of the influenza hemagglutinin antigen does not alter tumorigenicity in naïve but serves as a tumor-rejection target in immunized mice. T-cell-depletion experiments indicate that successful tumor protection can occur following immunization in mice depleted of CD4+ but not CD8+ T cells, suggesting that tumor protection is largely CD8-mediated and CD4-independent. Interestingly, despite the ability of tumor protection to be generated in the absence of CD4+ T cells, effective immunization was clearly dependent on CD40/CD40L as well as CD28/B7 interactions. 相似文献
8.
Kim MY Anderson G White A Jenkinson E Arlt W Martensson IL Erlandsson L Lane PJ 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(11):6686-6691
In this report, we have examined the expression of the T cell survival signals, OX40 ligand (OX40L) and CD30 ligand (CD30L) on CD4(+)CD3(-)CD11c(-)B220(-)IL-7Ralpha(+) inducer cells from birth to adulthood in mice. We found that adult but not neonatal inducer cells expressed high levels of OX40L and CD30L, whereas their expression of TNF-related activation-induced cytokine (TRANCE) and receptor activator of NF-kappaB (RANK) was comparable. The failure of neonatal inducer cells to express the ligands that rescue T cells helps to explain why exposure to Ag in neonatal life induces tolerance rather than immunity. The expression of OX40L and CD30L on inducer cells increased gradually in the first few weeks of life achieving essentially normal levels around the time mice were weaned. We found that IL-7 signaling through the common cytokine receptor gamma-chain was critical for the optimal expression of both TNF-related activation-induced cytokine and CD30L but not OX40L. Furthermore, glucocorticoids, which potently suppress T effector function, did not influence the expression of OX40L and CD30L in the presence of IL-7. 相似文献
9.
10.
Reyes-Moreno C Sharif-Askari E Girouard J Léveillé C Jundi M Akoum A Lapointe R Darveau A Mourad W 《The Journal of biological chemistry》2007,282(27):19473-19480
It is well established that the CD154/CD40 interaction is required for T cell-dependent B cell differentiation and maturation. However, the early molecular and structural mechanisms that orchestrate CD154 and CD40 signaling at the T cell/APC contact site are not well understood. We demonstrated that CD40 engagement induces the formation of disulfide-linked (dl) CD40 homodimers that predominantly associate with detergent-resistant membrane microdomains. Mutagenesis and biochemical analyses revealed that (a) the integrity of the detergent-resistant membranes is necessary for dl-CD40 homodimer formation, (b) the cytoplasmic Cys(238) of CD40 is the target for the de novo disulfide oxidation induced by receptor oligomerization, and (c) dl-CD40 homodimer formation is required for CD40-induced interleukin-8 secretion. Stimulation of CD154-positive T cells with staphylococcal enterotoxin E superantigen that mimics nominal antigen in initiating cognate T cell/APC interaction revealed that dl-CD40 homodimer formation is required for interleukin-2 production by T cells. These findings indicate that dl-CD40 homodimer formation has a physiological role in regulating bidirectional signaling. 相似文献
11.
CD40/CD40 ligand interactions are critical for elicitation of autoimmune-mediated fibrosis in the lung 总被引:7,自引:0,他引:7
Zhang-Hoover J Sutton A Stein-Streilein J 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(5):3556-3563
Pulmonary interstitial fibrosis (PIF), associated with persistent inflammation and increased collagen deposition in the interstitium, is often considered an autoimmune disease. Hapten immune PIF (HIPIF), a model for PIF, is elicited in the lung by a single intratracheal (i.t.) challenge in mice sensitized with hapten (2,4,6-trinitrobenzene sulfonic acid, TNBS). In this study, we characterized the role of CD40/CD40 ligand (CD40L) interactions in the elicitation of secondary cell-mediated immune responses that lead to development of fibrosis in the lung using an adoptive transfer model of HIPIF. The expression of CD40 was detected on bronchoalveolar lavage (BAL) cells 1-3 days after i.t. challenge with hapten in the HIPIF lung, but not lungs from the control mice. The CD40(bright) BAL cells morphologically resembled infiltrating monocytes. Furthermore, blocking CD40/CD40L interactions with blocking Ab decreased BAL production of Th1-mediators (IL-12 and TNF-alpha). Moreover, either blocking CD40/CD40L interactions with the Ab or using IL-12 knockout recipient mice prevented the increased collagen deposition (accumulation of hydroxyproline) in the lungs during HIPIF induction. We conclude that second signals (CD40/CD40L interactions) are required for elicitation of secondary immune responses that lead to PIF in vivo. The results support the notion that CD40/CD40L interactions are involved in the pathogenesis of an ongoing autoimmune disease. 相似文献
12.
Way SS Havenar-Daughton C Kolumam GA Orgun NN Murali-Krishna K 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(7):4498-4505
Differentiation of Ag-specific T cells into IFN-gamma producers is essential for protective immunity to intracellular pathogens. In addition to stimulation through the TCR and costimulatory molecules, IFN-gamma production is thought to require other inflammatory cytokines. Two such inflammatory cytokines are IL-12 and type I IFN (IFN-I); both can play a role in priming naive T cells to produce IFN-gamma in vitro. However, their role in priming Ag-specific T cells for IFN-gamma production during experimental infection in vivo is less clear. In this study, we examine the requirements for IL-12 and IFN-I, either individually or in combination, for priming Ag-specific T cell IFN-gamma production after Listeria monocytogenes (Lm) infection. Surprisingly, neither individual nor combined defects in IL-12 or IFN-I signaling altered IFN-gamma production by Ag-specific CD8 T cells after Lm infection. In contrast, individual defects in either IL-12 or IFN-I signaling conferred partial ( approximately 50%) reductions, whereas combined deficiency in both IL-12 and IFN-I signaling conferred more dramatic (75-95%) reductions in IFN-gamma production by Ag-specific CD4 T cells. The additive effects of IL-12 and IFN-I signaling on IFN-gamma production by CD4 T cells were further demonstrated by adoptive transfer of transgenic IFN-IR(+/+) and IFN-IR(-/-) CD4 T cells into normal and IL-12-deficient mice, and infection with rLm. These results demonstrate an important dichotomy between the signals required for priming IFN-gamma production by CD4 and CD8 T cells in response to bacterial infection. 相似文献
13.
Ruby CE Montler R Zheng R Shu S Weinberg AD 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(4):2140-2148
Engagement of OX40 greatly improves CD4 T cell function and survival. Previously, we showed that both OX40 engagement and CTLA-4 blockade led to enhanced CD4 T cell expansion, but only OX40 signaling increased survival. To identify pathways associated with OX40-mediated survival, the gene expression of Ag-activated CD4 T cells isolated from mice treated with anti-OX40 and -CTLA-4 was compared. This comparison revealed a potential role for IL-12 through increased expression of the IL-12R-signaling subunit (IL-12Rbeta2) on T cells activated 3 days previously with Ag and anti-OX40. The temporal expression of IL-12Rbeta2 on OX40-stimulated CD4 T cells was tightly regulated and peaked approximately 4-6 days after initial activation/expansion, but before the beginning of T cell contraction. IL-12 signaling, during this window of IL-12Rbeta2 expression, was required for enhanced T cell survival and survival was associated with STAT4-specific signaling. The findings from these observations were exploited in several different mouse tumor models where we found that the combination of anti-OX40 and IL-12 showed synergistic therapeutic efficacy. These results may lead to the elucidation of the molecular pathways involved with CD4 T cell survival that contribute to improved memory, and understanding of these pathways could lead to greater efficacy of immune stimulatory Abs in tumor-bearing individuals. 相似文献
14.
Gorbachev AV Heeger PS Fairchild RL 《Journal of immunology (Baltimore, Md. : 1950)》2001,166(4):2323-2332
The primary effector cells of contact hypersensitivity (CHS) responses to dintrofluorobenzene (DNFB) are IFN-gamma-producing CD8(+) T cells, whereas CD4(+) T cells regulate the magnitude and duration of the response. The requirement for CD40-CD154 engagement during CD8(+) and CD4(+) T cell priming by hapten-presenting Langerhans cells (hpLC) is undefined and was tested in the current study. Similar CHS responses to DNFB were elicited in wild-type and CD154(-/-) animals. DNFB sensitization of CD154(-/-) mice primed IFN-gamma-producing CD8(+) T cells and IL-4-producing CD4(+) T cells. However, anti-CD154 mAb MR1 given during hapten sensitization inhibited hapten-specific CD8(+), but not CD4(+), T cell development and the CHS response to challenge. F(ab')(2) of MR1 failed to inhibit CD8(+) T cell development and the CHS response suggesting that the mechanism of inhibition is distinct from that of CD40-CD154 blockade. Furthermore, anti-CD154 mAb did not inhibit CD8(+) T cell development and CHS responses in mice depleted of CD4(+) T cells or in CD4(-/-) mice. During in vitro proliferation assays, hpLC from mice treated with anti-CD154 mAb during DNFB sensitization were less stimulatory for hapten-primed T cells than hpLC from either control mice or mice depleted of CD4(+) T cells before anti-CD154 mAb administration. These results demonstrate that development of IFN-gamma-producing CD8(+) T cells and the CHS response are not dependent on CD40-CD154 interactions. This study proposes a novel mechanism of anti-CD154 mAb-mediated inhibition of CD8(+) T cell development where anti-CD154 mAb acts indirectly through CD4(+) T cells to impair the ability of hpLC to prime CD8(+) T cells. 相似文献
15.
The CD40-CD40 ligand (CD40L) system (CD154) is a central means of immune cell communication crucial for Ig class switching and enhanced Ag presentation. CD40 is also a key signaling conduit to activate nonhematopoietic cells, such as fibroblasts and endothelial cells, to produce proinflammatory mediators. Disruption of the CD40-CD40L pathway reduces lung inflammation and fibrosis, autoimmune disease and atherosclerosis. Non-bone marrow-derived structural cells are not known to express CD40L. In this study, we reveal the intriguing finding that primary strains of human lung fibroblasts derived from normal and scarred lung express both CD40L mRNA and protein. Interestingly, CD40L expression is down-regulated by IFN-gamma, a type 1 cytokine with antiscarring properties, and is up-regulated by the profibrogenic type 2 cytokine IL-13. Flow cytometry and laser confocal microscopy revealed that the majority of CD40L was located intracellularly. Importantly, fibroblast strains from human idiopathic pulmonary fibrosis tissue expressed increased levels of CD40L compared with fibroblasts from nonscarred lung. Fibroblasts in the scarred areas of human lung tissue expressed high levels of CD40L. Finally, the blood and lung lavage levels of CD40L are significantly elevated in fibrosis patients compared with normals. These new findings demonstrate that fibroblasts are a new source of CD40L and that those involved in scarring may have undergone a selected expansion for high CD40L expression. Moreover, the antifibrotic activity of IFN-gamma may involve the down-regulation of fibroblast CD40L levels. We speculate that fibroblast-derived CD40L plays a role in promoting fibroblast activation and possibly in interaction with CD40 bearing cells. 相似文献
16.
Subauste CS Subauste A Wessendarp M 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(3):1645-1653
CD40-CD154 interaction is pivotal for cell-mediated immunity. There are contradictory reports on whether HIV-1 infection impairs CD154 induction. The interaction between CD40 and CD154 is important not only because it results in activation of APCs but also because it controls CD154 by diminishing expression of this molecule. Compared with healthy controls, CD4(+) T cells from HIV-1(+) patients had impaired induction of CD154 when T cell activation was mediated by CD40(+) APCs. In contrast, T cell activation in the absence of these cells resulted in normal CD154 expression. CD154 induction in HIV-1(+) patients and controls were similar upon blockade of CD40-CD154 binding. Defective regulation of CD154 appeared to occur downstream of the control of mRNA levels because up-regulation of CD154 mRNA was not impaired by HIV-1 infection. This work identifies CD40 as a mediator of impaired CD154 induction in HIV-1 infection and explains why this defect was not detected by studies where T cell activation was triggered independently of CD40(+) APCs. In addition, dysregulation of CD154 in HIV-1 infection likely contributes to immunodeficiency because diminished expression of CD154 induced by CD40 is of functional relevance, resulting in decreased dendritic cell maturation. 相似文献
17.
Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis 总被引:7,自引:0,他引:7
O'Neill SK Shlomchik MJ Glant TT Cao Y Doodes PD Finnegan A 《Journal of immunology (Baltimore, Md. : 1950)》2005,174(6):3781-3788
B cells play an important role in rheumatoid arthritis, but whether they are required as autoantibody-producing cells as well as APCs has not been determined. We assessed B cell autoantibody and APC functions in a murine model of autoimmune arthritis, proteoglycan (PG)-induced arthritis, using both B cell-deficient mice and Ig-deficient mice (mIgM) mice that express an H chain transgene encoding for membrane-bound, but not secreted, IgM. The IgH transgene, when paired with endogenous lambda L chain, recognizes the hapten 4-hydroxy-3-nitro-phenyl acetyl and is expressed on 1-4% of B cells. B cell-deficient and mIgM mice do not develop arthritis after immunization with PG. In adoptive transfer of PG-induced arthritis into SCID mice, T cells from mIgM mice immunized with PG were unable to transfer disease even when B cells from PG-immunized wild-type mice were provided, suggesting that the T cells were not adequately primed and that Ag-specific B cells may be required. In fact, when PG was directly targeted to the B cell Ig receptor through a conjugate of 4-hydroxy-3-nitrophenyl acetyl-PG, T cells in mIgM mice were activated and competent to transfer arthritis. Such T cells caused mild arthritis in the absence of autoantibody, demonstrating a direct pathogenic role for T cells activated by Ag-specific B cells. Transfer of arthritic serum alone induced only mild and transient arthritis. However, both autoreactive T cells and autoantibody are required to cause severe arthritis, indicating that both B cell-mediated effector pathways contribute synergistically to autoimmune disease. 相似文献
18.
Cutting edge: CD4 is not required for the functional activity of IL-16 总被引:11,自引:0,他引:11
Mathy NL Bannert N Norley SG Kurth R 《Journal of immunology (Baltimore, Md. : 1950)》2000,164(9):4429-4432
IL-16 functions as a chemoattractant factor, inhibitor of HIV replication, and inducer of proinflammatory cytokine production. Previous studies have suggested that CD4 is the receptor for IL-16, because only CD4+ cells respond to IL-16 and both the anti-CD4 Ab OKT4 and soluble CD4 can block IL-16 function. However, these are only indirect evidence of a requirement for CD4, and to date a direct interaction between IL-16 and CD4 has not been shown. In this paper, we report that cells from CD4 knockout mice are as responsive to IL-16 as their CD4 wild-type equivalents in both assays testing for IL-16 function (chemotaxis and production of proinflammatory cytokines). In addition, the inhibitory effect of soluble CD4 on IL-16 function observed using CD4 wild type murine cells was not observed using CD4 knockout cells. These data demonstrate that CD4 is not required for IL-16 function and suggest that another molecule acts as the major receptor. 相似文献
19.
IL-2 is not required for the initiation of CD8 T cell cycling but sustains expansion 总被引:6,自引:0,他引:6
Based primarily on in vitro data, IL-2 is believed to be the key cytokine for initiation of the cell cycle of activated T cells. However, the role of IL-2 remains unresolved for T cell responses in vivo. We examined whether the absence of IL-2-mediated signaling in CD8 T cells affected initiation of proliferation. Our results conclusively demonstrated that initial division of Ag-specific CD8 T cells following priming was IL-2 independent, regardless of the context in which Ag was presented. In contrast, the latter stage of the proliferative phase was IL-2-dependent, particularly in nonlymphoid tissues. Thus, activated CD8 T cells initially undergo IL-2-independent proliferation, but reach a critical juncture where the requirement for IL-2 as a growth factor gains prominence. 相似文献
20.
Reyes-Moreno C Girouard J Lapointe R Darveau A Mourad W 《The Journal of biological chemistry》2004,279(9):7799-7806
Preformed CD40/CD40 homodimers were initially observed on human Burkitt lymphoma cell lines, normal B cells, and transitional bladder carcinoma cell lines. However, the nature and the biological relevance of these homodimers have not yet been investigated. In the present study, we demonstrated that Epstein-Barr virus-transformed B cells and CD40-transfected HEK 293 cells constitutively expressed disulfide-linked CD40/CD40 homodimers at low levels. Oligomerization of CD40 leads to a rapid and significant increase in the disulfide-linked CD40/CD40 homodimer formation, a response that could be prevented using a thiol-alkylating agent. Formation of CD40/CD40 homodimers was found to be absolutely required for CD40-mediated activation of phosphatidylinositol 3-kinase, which, in turn regulated B7.2 expression. In contrast, CD40 monomers provided the minimal signal emerging from CD40, activating p38 MAP kinase and inducing homotypic B cell adhesion. CD40/CD40 homodimer formation was totally independent of TRAF1/2/3/5 associations with the threonine at position 254 in the cytoplasmic tail of the CD40 molecules. This finding may be vital to better understanding the molecular mechanisms that govern cell signaling triggered by CD40/CD154 interactions. 相似文献