Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous evidence from several laboratories suggests that CD8+ T suppressor cells may be important regulatory elements governing specific unresponsiveness of lepromatous lepromatous leprosy patients to M.leprae. To analyse the mechanism of suppression, CD8+ Ts clones were established from lesions and peripheral blood of lepromatous patients and tested for ability to suppress antigen-responsive CD4+. Th clones or PBL. Suppression required induction by specific M.leprae antigen, but was effected in an antigen-non-specific fashion. The Ts clones failed to exhibit cytotoxicity of four antigen-exposed MHC-matched target cells: (i) an ori-SV40 transformed macrophage line; (ii) EBV transformed B cell lines; (iii) primary macrophages; and (iv) M.leprae responsive CD4+ cells. The possibility that Ts clones induce functional inactivation of CD4+ clones in vitro was investigated. M.leprae-responsive CD4+ clones were preincubated with Ts CD8+ clones, APC, and antigen for 16 h, after which the CD8+ cells were removed. The CD4+ clones with M.leprae and APC remained unresponsive to restimulation with APC and antigen for at least 10 days, although they responded to IL-2. Addition of IL-2 to the pre- or post-incubation cultures neither prevented the induction of unresponsiveness, nor reversed it. Earlier models of tolerance have suggested that receptor occupancy in the absence of second signals induces tolerance in B and T cells. Under conditions in which antigen responses of Th clones were HLA-DR-restricted, the Ts clones were able to suppress the response of DR mismatched Th clones. Thus, the effect of the Ts cells, like mechanisms requiring antigen presentation without a second signal, appears to be induction of clonal anergy in Th cells, perhaps by a novel mechanism.
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PMID:On the mechanism of human T cell suppression. 253 60

Recently, it has been demonstrated that lymphocyte function-associated Ag (LFA-3) is a natural ligand for CD2 and that this receptor-ligand interaction functions in cell-cell adhesion. In this report, we demonstrate that LFA-3 plays a role in T cell activation. L cells were transfected with human genomic DNA and sorted for expression of LFA-3. We demonstrate that LFA-3+ L cells, together with anti-CD3 mAb or with suboptimal doses of PHA, stimulate proliferation of human peripheral blood T cells. Furthermore, thymocyte proliferation was induced by LFA-3+ L cells and suboptimal doses of PHA. Proliferation was inhibited by mAb directed against either CD2 or LFA-3. Stimulation of thymocytes by the combination of PHA and LFA-3+ L cells resulted in the increased expression of the IL-2R, as well as of the surface Ag 4F2, transferrin receptor, and HLA-DR. These data support the conclusion that LFA-3 plays a role in CD2-dependent T cell activation. LFA-3 is widely distributed and is expressed on all APC and target cells. Thus, the ability of the CD2/LFA-3 interaction to costimulate with an anti-CD3 mAb suggests that the CD2/LFA-3 interaction may be involved not only in an Ag-independent alternate pathway of T cell activation but also in Ag-specific T cell activation.
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PMID:Interaction of CD2 with its ligand, LFA-3, in human T cell proliferation. 283 37

Participation of two of three distinct human Ia molecules, HLA-DR and the Ia molecule detected by monoclonal antibody (MoAb) 1B4 (1B4 molecules), in antigen presentation for T cell responses to purified protein derivative (PPD) and herpes simplex virus (HSV) was first suggested from studies on the inhibition of proliferative responses of whole T cell populations with MoAb against human Ia molecules. To determine whether a single T cell recognizes the antigen in the context of both Ia molecules or in the context of each one of two Ia molecules, we isolated and propagated PPD-reactive T cell clones from an HLA-DR heterozygous individual. The clones showed four different restriction patterns: type I and type II clones appeared to be restricted to one of two HLA-DR antigens, type III clones gave anomalous patterns of response and seemed to be restricted to non-DR antigens, and type IV clone recognized antigen when both DR antigens were presented on the same APC surface. Blocking study with MoAb to Ia molecules suggested that type I and type II clones are restricted to DR molecules and type III clones are restricted to 1B4 molecules distinct from DR or MB1 molecules. Furthermore, it is most likely that type IV clone was restricted to the interaction molecule associated with DR antigens. These data imply that human T cell clones recognizing PPD in the context of each one of two Ia molecules are clonally distinct.
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PMID:Clonal distribution of human T cells recognizing PPD in the context of each of two distinct Ia molecules. 608 45

We investigated possible explanations for the common occurrence of perivenular lesions in liver allografts of patients on FK506 within a few weeks to several months after OLT. Hematoxylin and eosin-stained sections of pre- and postperfusion biopsy specimens and day 7 post-transplant protocol biopsy specimens from 31 patients, randomly assigned to either FK506 or CsA as primary immunosuppressive agent, were reviewed, and immunohistochemical stains for HLA-DR antigen and S-100 protein were performed by the avidin-biotin peroxidase complex method. The histologic features of cellular rejection in the portal tracts of day 7 posttransplant allograft biopsy specimens from patients on FK506 were milder than those from patients on CsA. Immunohistochemical stains for HLA-DR showed intense positivity in a variety of cell types in day 7 posttransplant specimens from both groups, including sinusoidal-lining cells, bile duct epithelial cells, vascular endothelial cells, inflammatory cells, and occasional injured hepatocytes. Although diffuse lobular staining was seen in the majority of cases in both groups, either with or without rejection, liver biopsy specimens from patients on FK506 showed concentration of positively stained cells in perivenular regions more often, and at a lower overall histologic grade of rejection, than specimens from patients on CsA. There were no differences in the number and distribution of S-100 protein-positive dendritic APC between biopsy specimens from FK506 versus CsA-treated patients, or between specimens with and without cellular rejection in either group. It is suggested that the development of perivenular injury, which is seen frequently in allograft biopsy specimens from patients on FK506 obtained at various intervals after transplantation, may be related to drug toxicity rather than to the process of allograft rejection.
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PMID:FK506 versus cyclosporine as primary immunosuppressive agent for orthotopic liver allograft recipients. Histologic and immunopathologic observations. 750 52

In addition to the interaction between the TCR and the MHC/Ag complex on the APC, optimal T cell activation also requires interaction between adhesion molecules on the APC and their ligands on T cells. We determined the presence of adhesion molecules on human epidermal Langerhans cells (LC) and their role in Ag-specific T cell activation. Freshly isolated LC did not display ICAM-1 (CD54), ICAM-2, LFA-1 (CD11a), and LFA-3 (CD58), as detected by double-color FACS analysis, using HLA-DR expression for LC identification. Upon culture, LC clearly expressed ICAM-1 and LFA-3, both already detectable after 1 day, reaching a plateau at day 2. ICAM-2 and LFA-1 were undetectable on cultured LC and attempts to induce this expression by different culture conditions remained unsuccessful. mAb against ICAM-1, LFA-1, LFA-3, and CD2, continuously present during culture, inhibited the T cell proliferative response to Candida albicans presented by cultured LC. Pretreatment of LC and/or T cells with mAb indicated that anti-ICAM-1 and anti-LFA-3 inhibited at the LC level, whereas anti-LFA-1 and anti-CD2 inhibited at the T cell level. The mAb-induced inhibition was dose-dependent, but a total blockade of the response was never achieved. Time-course observations revealed that ICAM-1 and LFA-3 on LC only functioned during the initiation phase of T cell activation. Our study demonstrates that both ICAM-1 and LFA-3 on LC considerably contribute to the generation of a T cell response. The high expression of these accessory molecules enable LC, at least in part, to perform their powerful Ag-presenting function.
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PMID:Function of adhesion molecules lymphocyte function-associated antigen-3 and intercellular adhesion molecule-1 on human epidermal Langerhans cells in antigen-specific T cell activation. 751 46

Dendritic cells (DC) are the principle APC involved in primary immune responses; their major function is to obtain Ag in tissues, migrate to lymphoid organs, and activate T cells. DC are also the first immune cells to arrive at sites of inflammation on mucous membranes, the major site of sexual transmission of HIV. We have demonstrated previously that three populations of cells that can develop a dendritic morphology are present in peripheral blood. Two of these populations can express CD83, a marker of DC, and appear to be at different stages of maturation: 1) a precursor population and 2) a mature immunostimulatory DC. Precursor-derived DC express high levels of CD86 (B7-2) and HLA-DR but no CD80 (B7-1), whereas mature DC have high levels of expression of all three markers. Mature DC in peripheral blood bind HIV to their surface and induce infection when added to autologous CD4+ T cells in the absence of added stimuli, such as mitogens. These mature DC, when isolated directly from peripheral blood, appear to be conjugated to T cells, and these conjugates are infected easily and productively with HIV. These findings suggest a role for DC in early HIV infection in which they bind virus and interact with T cells locally or after migrating to a lymphoid organ, thus establishing a productive infection. Furthermore, they likely play a role in the propagation of HIV infection by activating T cells in the presence of HIV, which leads to viral replication and immune cell destruction.
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PMID:Both a precursor and a mature population of dendritic cells can bind HIV. However, only the mature population that expresses CD80 can pass infection to unstimulated CD4+ T cells. 756 Nov 24

The B7 molecule is expressed by APC that can costimulate T cells by binding the T cell surface receptors CD28 and CTLA-4. The human epidermal Langerhans cell (LC) is one of the most potent APC, yet B7 expression by this cell type has not previously been assessed. We used a CTLA4-Ig fusion protein that binds B7 with high avidity to probe cell surface expression of B7 by cultured and noncultured LC. LC cultured for 1 or more days were specifically stained with biotinylated CTLA4-Ig and fluorescent streptavidin. In contrast, binding of CTLA4-Ig to freshly isolated LC was not detected. The cell surface distributions of B7 and of HLA-DR on cultured LC differed, as CTLA4-Ig binding was localized to discrete foci, whereas anti-DR mAb uniformly stained the LC plasma membrane. Analyses of epidermal cell (EC) mRNA indicated that the B7 gene is expressed by these cells. Thus, B7 gene probes specifically hybridized to polymerase chain reaction-amplified B7 mRNA isolated from cultured and noncultured EC. As LC are the only normal epidermal cell type that induces proliferation of allogeneic T cells, the role of B7 in this LC function was studied by coculturing highly purified resting CD4+ T cells and allogeneic EC in the presence of CTLA4-Ig, anti-CD54 (RR/1, anti-intercellular adhesion molecule-1) mAb, or both. CTLA4-Ig and RR/1 each inhibited CD4+ T cell responses to freshly isolated allogeneic EC, and cooperative inhibition of more than 90% was observed in cultures treated with both CTLA4-Ig and RR/1 at 5 micrograms/ml. CTLA4-Ig inhibited stimulation by either fresh EC or cultured EC, suggesting that the increased potency of cultured LC vs noncultured LC may reflect the time needed for noncultured LC to express cell surface B7 in vitro. These studies indicate that B7 is expressed on the cell surface of cultured LC, and that LC B7 costimulates the proliferation of resting allogeneic CD4+ T cells.
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PMID:Expression and function of B7 on human epidermal Langerhans cells. 767 25

The CD28 pathway functions to provide costimulatory signals that are required for TCR-mediated activation of T cells. The role of this pathway in superantigenic stimulation of resting human T cells was investigated in the presence and absence of APC using a streptococcal superantigen, pep M5. Anti-B7/BB1 mAb inhibited the response of T cells when pep M5 was presented by APC. In the absence of APC, cross-linking CD28 by anti-CD28 mAb provides signals that synergize with APC-derived cytokines and with superantigen resulting in T cell proliferation. Anti-HLA-DR, -DQ mAb blocked the response of T cells to pep M5 presented by APC but had no effect on the response of purified T cells to the superantigen costimulated via CD28 cross-linking. These data show that the CD28 pathway is important for superantigenic stimulation of T cells and that signaling through this pathway can substitute for the APC-associated costimulatory activity that is essential for T cell stimulation. Moreover, the results are consistent with the notion that, in the presence of appropriate costimulation, pep M5 can directly interact with T cells and induce them to proliferate.
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PMID:CD28 delivers costimulatory signals for superantigen-induced activation of antigen-presenting cell-depleted human T lymphocytes. 768 35

APC dysfunction may be important in immune dysregulation associated with HIV disease. Langerhans cells, epidermal APC, can be infected with HIV, although their function in HIV-infected persons has not been studied. Therefore, we studied the immunologic function of Langerhans cells, in parallel with blood APC (enriched for monocytes/macrophages (M phi) function, in 21 HIV-seropositive (HIV+) and 21 HIV-seronegative volunteers, including three monozygotic twin pairs discordant for HIV serology. Langerhans cells from HIV+ patients were quantitatively normal and expressed normal levels of HLA-DR. However, Langerhans cells from AIDS patients and M phi from both AIDS and HIV+ non-AIDS patients stimulated allogeneic T cells less well compared with control APC. In addition, decreased recall Ag- and mitogen-induced T cell responsiveness was observed in HIV+ patients using either autologous Langerhans cells or autologous M phi as APC/accessory cells. Interestingly, Langerhans cells and M phi isolated from HIV+ twins (CD4+ cell counts of 181, 271, and 562/mm3) were able to present recall Ag normally to HIV-uninfected syngeneic T cells. In summary, APC from HIV+ patients were impaired in their ability to generate a primary immune response (i.e., alloantigen-induced T cell stimulation), but they retained the ability to generate a secondary immune response (i.e., recall Ag-induced syngeneic T cell stimulation). Thus, these findings suggest that defects in secondary immune responses commonly observed in HIV disease are dependent on T cell dysfunction alone, whereas defective primary immune responses may be secondary to both T cell and APC dysfunction.
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PMID:Functional studies of epidermal Langerhans cells and blood monocytes in HIV-infected persons. 789 31

We characterized the response of resting human CD8 T cells to allogeneic endothelial cells (EC). Both resting and IFN-gamma-pretreated EC stimulate similar CD8 T cell proliferative responses (peak, day 5 to 6), whereas only IFN-gamma-pretreated EC stimulate CD4 T cells. The response increases with increasing numbers of CD8 T cells from 25,000 to 400,000/well. The proliferation of CD8 T cells is inhibited by mAbs reactive with CD8 or HLA-A and -B molecules but not with CD4 or HLA-DR. mAb blocking studies show a role for CD2, LFA-3, and CD59, but not for intercellular adhesion molecule-1, intercellular adhesion molecule-2, very late activation Ag-4, vascular cell adhesion molecule-1, CD28, or CD28 ligand, as costimulatory molecules. The stimulation of resting CD8 T cells by EC causes secretion of IL-2 and IFN-gamma but not IL-4. Both proliferation and IFN-gamma secretion are inhibited by mAb to the IL-2R alpha subunit (CD25). Limiting dilution analysis suggests that approximately 1 in 20,000 resting CD8 T cells secrete IL-2 in response to allogeneic EC. EC stimulate greater than 1 in 10,000 CD8/CD45RO+ cells but fewer than 1 in 40,000 CD8/CD45RA+ cells, which indicates that primarily memory CD8 T cells respond to EC. Coculturing CD8 cells with EC stimulates a sufficient level of endothelial class II MHC expression to subsequently support a CD4 T cell proliferative response. The ability of memory CD8 T cells to proliferate against allogeneic EC, a nonclassical APC, and their ability to stimulate EC may contribute to the initiation of vascularized organ graft rejection.
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PMID:Antigen-presenting function of human endothelial cells. Direct activation of resting CD8 T cells. 798 46


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