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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because UV-induced epidermal macrophages (UV-Mph) preferentially activate CD4+ T suppressor-inducer cells and induce tolerance, we hypothesized that they differentially up-regulate T cell early activation genes compared with constitutive epidermal APC, Langerhans cells. We used epidermal cells from UV-exposed (UV-EC) and control (C-EC) human skin to stimulate allogeneic CD4+ T lymphocytes. Reverse transcriptase-PCR revealed that both C-EC (Langerhans cells) and UV-EC (UV-Mph) induced 10(3)- to 10(6)-fold increases in IL-2 mRNA. However, while T cells stimulated by C-EC for 48 h showed a greater than 10(3)-fold increase in IL-2R alpha mRNA, those stimulated by UV-EC did not (n = 5, p = 0.004). Flow cytometry demonstrated that 4.1 +/- 2.3% of unstimulated CD4+ lymphocytes expressed cell surface IL-2R alpha, which increased to 15.7 +/- 1.8% upon stimulation by C-EC for 48 h, but stimulation by UV-EC failed to increase the IL-2R alpha+ population (n = 3, p = 0.038). The addition of neutralizing anti-TGF-beta Abs to UV-EC-stimulated cultures restored CD4+ cell surface IL-2R alpha expression to 12.9 +/- 0.2%. CD4+ T cell activation by UV-Mph is distinct from previously described models of tolerance such as Th2 activation (IFN-gamma mRNA was induced and IL-4 mRNA was not) and Th1 anergy (IL-2 mRNA levels induced by UV-EC and C-EC were similar). Furthermore, costimulatory signals were provided by UV-Mph; CTLA4-Ig and LFA-3-Ig fusion proteins and Abs to CD2, LFA-3, LFA-1, and ICAM-1 inhibited UV-Mph-induced T cell proliferation. Thus, the altered immune outcome induced by UV-Mph (tolerization) compared with Langerhans cells (sensitization) is reflected as a novel mechanism of initial CD4+ T cell early activation gene expression characterized by TGF-beta-dependent deficient IL-2R alpha expression.
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PMID:Suppressor T cell-activating macrophages in ultraviolet-irradiated human skin induce a novel, TGF-beta-dependent form of T cell activation characterized by deficient IL-2r alpha expression. 749 43

The mechanisms underlying the induction of immunological tolerance after feeding soluble exogenous antigens, including proteins and haptens, are still unclear. Using a model of oral tolerance to the contact-sensitizing hapten 2,4-dinitrochlorobenzene (DNCB), we have compared the ability-of intestinal epithelial cells and of Peyer's patch APC to present DNCB in vitro or ex vivo after oral feeding, to specific peripheral lymph node T cells from DNCB-sensitized mice. In contrast to Peyer's patch APC, which induce efficient hapten-specific T cell activation upon exposure to the hapten either in vitro or in vivo, mature MHC class-II-positive intestinal epithelial cells were unable to induce T cell activation in either case. Interestingly, enterocytes from DNCB-fed mice exerted a dramatic inhibitory effect on the proliferative response of hapten-primed T cells in response to dinitrobenzene sulfonate presented by syngeneic spleen cells. This inhibitory effect, which was also observed with supernatant of intestinal epithelial cells from DNCB-fed mice, could be reversed by neutralizing anti-transforming growth factor (TGF)-beta antibodies. In addition, pre-incubation of hapten-sensitized T cells with enterocytes from DNCB-fed mice induced T cell anergy, which could be reversed by exogenous interleukin-2 or interleukin-4. These data demonstrate that intestinal epithelial cells activated in vivo by oral administration of DNCB are able to block proliferation of activated T cells through secretion of immunosuppressive cytokines such as TGF-beta. It is proposed that intestinal epithelial cells may play a significant role in oral tolerance by limiting T cell-mediated hypersensitivity responses.
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PMID:Oral tolerance to haptens: intestinal epithelial cells from 2,4-dinitrochlorobenzene-fed mice inhibit hapten-specific T cell activation in vitro. 777 42

We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.
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PMID:A benign cultured colon adenoma bears three genetically altered colon cancer oncogenes, but progresses to tumorigenicity and transforming growth factor-beta independence without inactivating the p53 tumor suppressor gene. 813 40

Nonhybridized CD8+ Ts cell clones were generated from individual spleen cells of a B6D2F1 mouse, which had been immunosuppressed in an antigen-specific manner by administration of tolerogenic conjugates of ovalbumin (OVA) and monomethoxypolyethylene glycol. The cloned Ts cells were shown to suppress both in vivo and in vitro anti-OVA antibody formation in an antigen-specific and isotype-nonspecific manner, i.e., IgM, IgG1, and IgG2a anti-OVA antibodies were suppressed. The cytokine profile of three Ts cell clones was determined by bioassays, Western blot, and polymerase chain reaction analyses. It was shown that all the Ts cell clones produced IL-2, IL-4, IFN-gamma, TGF-beta 1, LT, and TNF-alpha upon activation with hamster anti-CD3 monoclonal antibody (mAb) or antigen plus APC. However, neither the mAbs to IFN-gamma, TGF-beta, or LT/TNF-alpha, nor the recombinant IL-2 was able to abrogate the suppression of in vitro antibody production by cloned Ts cells. These data are taken to indicate that (i) the cloned Ts cells suppress anti-OVA antibody production both in vivo and in vitro in an isotype-nonrestricted manner, (ii) the cytokine profile of these cloned Ts cells is similar to that of Th0 cells, and (iii) the immunosuppression mediated by these T cells is not directly related to the cytokines produced by cloned Ts cells.
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PMID:Cytokine gene expression of CD8+ suppressor T cells induced by tolerogenic conjugates of antigen and mPEG. 833 Mar 17

In murine contact photosensitivity, a cutaneous delayed-type hypersensitivity reaction, preirradiation of the photosensitization site with UVB induced Ag-specific, afferent limb-acting, CD4+CD8- suppressor T cells (Ts). The present study examined usage of TCR V beta and production of immunosuppressive cytokines in Ts propagated in vitro. Spleen cells from UVB-preirradiated, 3,3',4',5- tetracholorosalicylanilide (TCSA)-photosensitized mice were stimulated with 3000-rad-irradiated lymph node cells (LNC) from TCSA/UVA-sensitized mice (LNCTCSA) in the presence of rIL-t. After several rounds of antigenic stimulation, a T cell line (B+TCL) consisted exclusively of CD3+CD4+CD8- V beta 7+ and V beta 13+ populations. Transfer to naive recipients of B+TCL treated with anti-V beta mAb plus complement revealed that the V beta 7+ cells suppressed both the in vivo and the in vitro aspects of contact photosensitivity to TCSA in an Ag-specific manner. The in vitro suppressive activity of B+TCL was neutralized by anti-IL-10 mAb, but not by anti-IL-4 mAb, indicating a crucial role of IL-10 in UBV-induced suppression. Upon stimulation with 3000-rad-irradiated-LNCTCSA, B+TCL released IL-4 and IL-10 but not IL-2, and V beta 7+ cells produced IL-10. The reverse transcriptase-PCR detected mRNA for IL-4 and IL-10 but not that for IL-2, IFN-gamma, or TGF-beta in B+TCL stimulated with or without concanavalin A. In accordance with the findings in B+TCL, spleen cells from UVB preirradiation plus TCSA/UVA mice contained V beta 7+ T cells that suppressed contact photosensitivity to TCSA and produced substantial amounts of IL-4 that provided a microenvironment for Th2 cell generation. We conclude that UVB preirradiation and photosensitization result in the generation of V beta 7+ Th2 cells that suppress contact photosensitivity by releasing IL-10. The dysfunction of effector Th1 cells underlying UVB suppression of delayed-type hypersensitivity seems to be due not only to altered APC function but also to counteraction of Th2 cells by Th1 cells.
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PMID:TCRV beta 7+ Th2 cells mediate UVB-induced suppression of murine contact photosensitivity by releasing IL-10. 859 33

To assess a potential immunoregulatory role of Schwann cells in the peripheral nervous system we examined whether they are able to secrete nitric oxide metabolites. Schwann cells treated with IFN-gamma and TNF-alpha upregulated iNOS-specific mRNA within 12 hr and released nitrite in a time- and dose-dependent manner, reaching a plateau of secretion after 3 days. Nitrite secretion was inhibited by NMMA, suggesting that Schwann cells are endowed with a cytokine-inducible NO synthase. TGF-beta and IL-1 failed to modulate nitrite release. When assessing their role as APC, we note that Schwann cells activated CD4+ antigen-specific T-cell lines, but in contrast to professional thymic APC this ability declined markedly after Day 1. Theoretically diminished T-cell proliferation and finally death might be achieved by secretion of nitric oxide metabolites by Schwann cells. Inhibition of NO production by NMMA did not restore T-cell proliferation after Day 2 or prevent apoptosis of T-cells. However, in a coculture model Schwann cells exerted a strong suppressive effect on T-cell activation by thymic APC, which was almost completely abrogated by addition of NMMA. We suggest that Schwann cells may exert potent immunoregulatory functions beyond their role as APC. They may terminate immunoinflammatory reactions in the peripheral nervous system by releasing NO.
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PMID:Secretion of nitrite by Schwann cells and its effect on T-cell activation in vitro. 859 41

Organ graft rejection is caused by the recognition of allogeneic MHC molecules by recipient T cells by two different pathways. The indirect pathway of alloreactivity requires the presentation of MHC peptides from the graft by autologous APC, as with conventional antigen. The direct pathway, on the other hand, requires the recognition of foreign MHC on foreign cells. The regulatory mechanisms for this component of alloreactivity have not been extensively studied. We show here that the T cell response activated by alloantigens in the direct pathway is similarly constrained and modulated by cytokines, as has been shown for classic antigen presentation. Thus, the inclusion of IL-2 or TGF-beta in MLC performed with purified responder T cells resulted in outgrowth of cells secreting IL-2 and IFN-gamma, whereas addition of IL-4, IL-10, or anti-TGF-beta encouraged outgrowth of cells secreting IL-4 and IL-10. T cells alloactivated via the direct pathway and then cloned in IL-2 alone secreted IL-4 and IL-10 as well as IFN-gamma and IL-2 (Th0 phenotype). Established clones remained susceptible to cytokine modulation, such that IL-4 and IL-10 decreased their secretion of IL-2 and IFN-gamma, whereas TGF-beta suppressed IL-4 and IL-10 secretion. The first alterations of Th0 toward Th1 or Th2 phenotypes could already be observed after only a very brief exposure to cytokines of 48 hr, followed by extended culture with IL-2 alone. These results confirm that human T cells with Th1 and Th2 phenotypes, recognizing alloantigen via the direct pathway, derive from the same IL-2-secreting precursor and can be manipulated by cytokines in an analogous fashion to conventional antigen-reactive cells. These findings may have implications for manipulating the direct pathway of alloantigen recognition in human organ transplantation.
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PMID:Cytokine modulation of TH1/TH2 phenotype differentiation in directly alloresponsive CD4+ human T cells. 890 Mar 9

Recent investigations in antigen processing suggest that many hematopoietic and nonhematopoietic cell types are capable of presenting alloantigen to T lymphocytes. However, the role of certain nonclassical antigen presenting cells is blurred by their apparent ability to down-regulate the immune response as well as activate immune cells, depending upon the microenvironment and the functional state of the responding cells. In this study we examine the ability of cultured allogeneic keratinocytes to inhibit the response of naive T cells to alloantigen or to anti-CD3. Our results demonstrate that as few as 6.25 x 10(3) keratinocytes significantly inhibited T cell proliferation in response to alloantigen as well as anti-CD3-mediated stimulation (49 and 54%, respectively). HK-mediated inhibition of T cell proliferation did not require cell contact, suggesting that inhibition is mediated by cytokines or other soluble factors. This was further supported by experiments demonstrating the inducibility of HK inhibitory activity in the presence of FCS, and the partial blockage of HK inhibitory activity through the addition of indomethacin or anti-TGFbeta antibody. Interestingly, the data suggest that IL-10, a known immunomodulatory cytokine, does not play a role in the inhibitory activity seen in this system. Taken together the results suggest that HK have the potential to regulate the response of T cells to antigen presented by other APC through the production of soluble factors.
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PMID:Normal human keratinocytes inhibit the proliferation of unprimed T cells by TGFbeta and PGE2, but not IL-10. 901 84

Immune privilege in the eye is a dynamic state in which the immune response to ocular Ags is molded and modified by the eye itself. Immune privilege correlates with systemic alterations in the immune response such that deviant forms of immunity emerge. The eye itself contributes to immune deviation, in part by displaying unique immunoregulatory factors in aqueous humor and expressed on ocular cells. When T cells encounter Ag in the eye, they can become anergic, undergo apoptosis, secrete TGF-beta, and/or release soluble regulatory factors containing the TCR alpha-chain. Ags taken up by indigenous APC escape the eye and reach the spleen where they activate a unique spectrum of Ag-specific T and B cells. The absence of systemic delayed hypersensitivity and complement-fixing Abs in this deviant response probably relates to the fact that inflammation is deleterious to vision and leads to blindness. Immune privilege is the eye's way of protecting its vital function from the ravages of immunopathogenic injury.
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PMID:Immune deviation in relation to ocular immune privilege. 910 14

T cells from the intestinal mucosal proliferate poorly in vitro, and the contribution of Ag-specific recognition to this hyporesponsiveness is unclear, since the Ag repertoire of intestinal mucosal T cells is unknown. In this study, T cell proliferation in response to Ag-prepulsed autologous peripheral blood-derived APC was examined. Whereas T cells from peripheral blood proliferated to inner membrane and cytoplasmic Escherichia coli proteins, T cells from intestinal mucosa responded only to purified component Ags of these proteins and not to their combination. This suggests that the lack of proliferation in response to these Ags presented as a mixture is not due to the absence of E. coli-specific T cells in the mucosa, but, rather, to down-regulation after T cell recognition. Down-regulation was assayed by measuring the inhibition of autologous peripheral blood T cell proliferation in response to Ag-prepulsed APC. Coculture with leukocytes from intestinal mucosa and not from mesenteric lymph nodes, inhibited autologous peripheral blood T cell proliferation in response to E. coli proteins, but not to tetanus toxoid, PHA, or IL-2. Inhibition was independent of cell contact, provided APC were available to the mucosal cell population, and was reversible by neutralization of IL-10 or TGF-beta with mAb or depletion of mucosal CD4+ T cells. Taken together, the data suggest that mucosal T cell unresponsiveness to luminal Ags is mediated by production of inhibitory cytokines after specific Ag recognition by CD4+ T cells.
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PMID:CD4+ T cell down-regulation in human intestinal mucosa: evidence for intestinal tolerance to luminal bacterial antigens. 910 24


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