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

We recently identified three distinct T helper pathways which contribute to interleukin-2 (IL-2) production by human peripheral blood lymphocytes following stimulation with HLA alloantigens. In two of these pathways, CD4+ T helper cells respond to alloantigen using either self antigen-presenting cells (sAPC)* or allogeneic antigen-presenting cells (aAPC). A third pathway involves CD8+ T helper cells using aAPC. Previous in vitro studies have shown that the T helper pathway dependent on CD4+ T helper cells and sAPC (CD4-sAPC) is the most susceptible to suppression by cyclosporine. In the present study, we measured alloantigen-stimulated IL-2 production by PBL from 42 kidney transplant recipients to characterize the strength of the three T helper-APC pathways. In 58% of patients, a loss of the CD4-sAPC pathway was identified and was correlated with cyclosporine treatment. However, several patients not receiving cyclosporine also exhibited a similar loss of T helper cell function, suggesting that cyclosporine is not the only factor involved. Of 27 patients exhibiting depressed CD4-sAPC function, none had evidence of ongoing/recent graft rejection. In contrast, of 11 patients with no defects in the three pathways of in vitro T helper cell function, 6 had evidence of chronic graft rejection. Of considerable interest are the data obtained from a separate group of 4 patients who had episodes of acute rejection during the study. In each case, at the time of the rejection episode, all exhibited an intact CD4-sAPC pathway. However, samples tested prior to the rejection episode or after successful treatment of the rejection episode showed a depressed CD4-sAPC pathway. These results suggest that depression of the CD4-sAPC pathway represents adequate immunosuppression for graft retention and that patients not exhibiting such suppression are at increased risk for both acute and chronic graft rejection. These data may have relevance for diagnosis and/or prediction of graft rejection and may provide an in vitro method of monitoring the functional degree of immunosuppression in transplant recipients.
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PMID:Correlation of in vitro CD4+ T helper cell function with clinical graft status in immunosuppressed kidney transplant recipients. 167 59

Long-term lines of helper T (Th) cells, reactive to minor histocompatibility (minor-H) antigens, were grown by antigen restimulation in the absence of exogenous interleukin-2. These lines were antigen specific and H-2b restricted. When introduced in vivo by adoptive transfer, these Th cells helped syngeneic B cells in an antibody response to other alloantigens. Linked recognition was required for effective help to occur, this suggests B cell presentation of antigen to Th cells in vivo. Parallel titration experiments performed with long-term cultured Th lines to MHC and to minor-H antigens showed that, on a per cell basis, they are equivalent in their ability to help in vivo B cell responses. This shows that any inability to produce antisera to minor-H antigens is not due to a Th or APC defect, but results from either a B cell defect or from suppression.
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PMID:Helper T cell lines to major and to minor histocompatibility antigens are equally effective in the regulation of B cell responses in vivo. 614 22

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

Activation and proliferation of human T lymphocytes in vitro can be obtained by various stimuli including specific antigens, mitogens, and cytokines. Here we describe the effect of interleukin-10, interleukin-12 and tumor necrosis factor-alpha on the interleukin-2 dependent proliferation and function of established human CD4+ and CD8+ alloreactive T-cell clones in the absence of antigen presenting cells. IL-12 and TNF-alpha both demonstrated an inhibitory effect on the proliferation of CD8+ cytotoxic T lymphocyte clones, whereas IL-10 enhanced the proliferation. IL-12-induced inhibition of CD8+ CTL clones was not mediated by the endogenous production of TNF-alpha by these clones. The strong inhibitory effect of IL-12 and TNF-alpha did not result in apoptosis. These cytokines did not alter the cytotoxicity of CD8+ CTL clones. When CD4+ T-cell clones were tested in the absence of APC, no significant change in IL-2-dependent proliferation due to IL-10, IL-12, and TNF-alpha could be measured. Since these effects on established CTL clones are in contrast to the effects of IL-10, IL-12, and TNF-alpha during the induction phase of immune responses, a dichotomy of immunomodulatory cytokines such as IL-10, IL-12, and TNF-alpha early and late in the immune response is suggested.
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PMID:Interleukin-10, interleukin-12, and tumor necrosis factor-alpha differentially influence the proliferation of human CD8+ and CD4+ T-cell clones. 862 79

The aim of this study was to investigate the mechanisms by which B7-related costimulatory molecules (CD80, CD86) increase T-cell responsiveness to extracellular ligands. As a model study, the in vitro response of purified splenic CD4+ T cells to a bacterial superantigen, SEB, was characterized. Previous analysis of this experimental model led us to conclude that expression of B7-related molecules is strictly required in order to activate CD4+ T cells in the presence of bacterial superantigens. In the present report, we demonstrate that antigen-presenting cell-derived costimulatory signals regulate the kinetics of interleukin-2 (IL-2) production by SEB-activated splenic CD4+ T cells. Indeed, experiments performed with purified subpopulations of antigen-presenting cells and using B7-transfected cell lines indicated that increased levels of CD80 and/or CD86 cell surface expression is associated with a faster kinetics of IL-2 production in response to SEB. Accordingly, blocking of CD80 or CD86-derived signals by specific monoclonal antibodies led to a slower kinetics of IL-2 production in response to SEB. Thus these data demonstrate that similar strength of signal through the T-cell receptor can lead to immune responses displaying distinct kinetics depending on the level of costimulatory ligands on APC.
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PMID:Costimulation regulates the kinetics of interleukin-2 response to bacterial superantigens. 894 21

To characterize better the co-stimulatory activity of native B7-1 in the absence of other receptor/ligand interactions that might contribute to the response, B7-1 was purified by monoclonal antibody (mAb) affinity chromatography. Immobilization of purified B7-1 with anti-T cell receptor (TCR) mAb on cell-sized latex microspheres provided an effective stimulus for activation of both CD4+ and CD8+ T cells as measured by proliferation, development of effector function, and changes in motility and adhesion. The CD4+ T cell response was prolonged and resulted in efficient interleukin-2 production and clonal expansion. In contrast, CD8+ responses were transient. Proliferation and clonal expansion peaked on days 3 and 4, coincident with maximal expression of lytic effector function, and the cells then died. These results demonstrate that B7-1 mediated co-stimulation is sufficient for the induction of effector function in both helper and cytotoxic T cell precursors, but suggest that B7-1 co-stimulation is not sufficient to sustain helper-independent CD8+ CTL responses. When the dose responses of CD4+ and CD8+ T cells to B7-1 were compared, CD8+ T cells were found to require higher densities of B7-1 to attain an equivalent level of activation, suggesting that the level of expression of B7-1 by APC may influence the development of helper or CTL responses. Finally, in contrast to results obtained by others with B7-1 transfectants, purified B7-1 did not provide co-stimulation when presented on a surface separate from the TCR stimulus.
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PMID:B7-1-dependent co-stimulation results in qualitatively and quantitatively different responses by CD4+ and CD8+ T cells. 907 98

Recent studies in several laboratories have advanced the concept that during cellular rejection, the allograft undergoes a stress response which regulates the expression of stress proteins (or heat shock proteins, hsp) and triggers the recruitment and activation of hsp-reactive lymphocytes. In a rat model of heterotopic heart transplants we have found that allograft-infiltrating lymphocytes respond to recombinant mycobacterial hsp and irradiated syngeneic spleen cells as a source of self-APC (antigen-presenting cells). This report describes T cell clones generated by culturing ACI into Lewis rat cardiac allograft-derived lymphocytes with mycobacterial hsp71, syngeneic spleen cells and IL-2 (interleukin-2). Two groups of self-APC-reactive T cell clones have been distinguished, all of them are CD3+, CD4+, CD8-. One group is referred to as hsp71-dependent, autoreactive T cells because these clones respond to self-APC but only in the presence of hsp71. No reactivity is seen with mycobacterial hsp65 or when hsp71 is tested with allo-PC from ACI donors or third-party APC from Brown Norway (BN) rats. Treatment of hsp71 with trypsin, polymyxin B or ATP-agarose chromatography abrogates the hsp71 effect thus indicating that structurally intact hsp71 must interact with self-APC which then activate hsp71-dependent, autoreactive T cells. The second group of clones reacts to self-APC and while their response does not require the presence of hsp71, their proliferation is often augmented by hsp71 but not by hsp65. These hsp71-independent, autoreactive clones do not respond to allo-APC from ACI donors or third-party APC from BN rats. Polymyxin or trypsin treatment had no significant effect on their proliferative responses. The data with the anti-TCR-alpha beta monoclonal antibody R73 offer additional evidence for two functionally different types of self-APC reactive CD4 cells infiltrating the allograft. R73 inhibits the proliferation of self-APC induced responses of hsp-71-independent clones as well as the allo-APC induced responses of alloreactive T cell clones. In contrast, this antibody augments the responses of hsp71-dependent T cells. Moreover, these clones can also proliferate in response to self-APC when hsp71 is substituted by R73. The hsp71-dependency of self-APC reactive T cell reactivity represents a previously unrecognized mechanism of cellular immunity to allografts. This mechanism might be related to the peptide binding properties of hsp71 and the ability of stress proteins to function as molecular chaperones in antigen processing.
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PMID:Identification of two types of autoreactive T lymphocyte clones cultured from cardiac allograft-infiltrating cells incubated with recombinant mycobacterial heat shock protein 71. 910 36

T cell clones (B1, B21, B7, A25) specific to the soluble egg antigen (SEA) of Schistosoma japonicum were established from C3H/He mice immunized with SEA. These clones belonged to CD3+, CD4+ and CD8-Th1 cells, showing TCR-gamma delta-, TCR-alpha beta+ and Vbeta10b+. The molecular weights of target antigens recognized by the clones ranged from 51 to 80 kDa. Interleukin-2 (IL-2) and IL-12 could vigorously increase the proliferation response of the T clones to SEA; while IL-10 and transforming growth factor-beta1 (TGF-beta1) strongly inhibited the response. IL-12 activity was detected in the culture supernatant of T clones stimulated with SEA in the presence of APC (antigen presenting cells). This stimulation also upregulated the expression of the IL-12 receptor on the T clones. IL-12 from APC served as a costimulatory factor for the SEA induced proliferation of the T clone cells. Clone B1 was able to induce granuloma formation both in vivo and in vitro. These data provide further insight into the complicated interaction among SEA, T cell and cytokine at a clonal level in S. japonicum infection.
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PMID:Characterization of murine Th1 clones specific to egg antigen of Schistosoma japonicum and their interaction with cytokines. 1058 59

Mice immunized with peritoneal exudate cells (PEC; used as antigen-presenting cells [APC]) that are pulsed ex vivo with cryptococcal capsular polysaccharide, a glucuronoxylomannan (GXM), exhibit increased survival times and delayed-type hypersensitivity reactions when they are infected with Cryptococcus neoformans. These responses are GXM specific. The present study revealed that GXM-APC immunization enhanced development of anticryptococcal type-1 cytokine responses (interleukin-2 [IL-2] and gamma interferon) in mice infected with C. neoformans. The enhancement was not GXM specific, because immunization with GXM-APC and immunization with APC alone had similar effects. GXM-APC (or APC) immunization caused small increases in the expression of type-2 cytokines (IL-4 and IL-5), but the increases were not always statistically significant. IL-10 levels were not regulated by immunization with GXM-APC or APC. GXM-APC prepared with PEC harvested from mice injected with complete Freund's adjuvant (CFA) enhanced type-1 cytokine responses, while GXM-APC prepared with PEC induced with incomplete Freund's adjuvant were ineffective. The CFA-induced PEC had an activated phenotype characterized by increased numbers of F4/80(+) cells that expressed CD40, B7-1, and B7-2 on their membranes. The immunomodulatory activity of the CFA-induced APC population was not attributed to their production of IL-12 because GXM-APC prepared with peritoneal cells harvested from IL-12 knockout mice or their wild-type counterparts were equally effective in augmenting the type-1 response. Blocking of IL-12 in the recipients of GXM-APC early after APC infusion revealed that early induction of IL-12 secretion was not responsible for the immunomodulatory response elicited by GXM-APC. These data, considered together with previously reported data, reveal that the protective activity of GXM-APC immunization involves both antigen-specific and nonspecific activities of GXM-APC.
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PMID:Regulation of cytokine expression in mice immunized with cryptococcal polysaccharide, a glucuronoxylomannan (GXM), associated with peritoneal antigen-presenting cells (APC): requirements for GXM, APC activation, and interleukin-12. 1094 38

CD43 is a large heavily glycosylated protein highly expressed on T cells and actively excluded from the immunological synapse through interactions with ezrin-radixin-moesin proteins. Due to its size and charge, it has been proposed that the CD43 ectodomain acts as a physical barrier to T cell-APC interactions. We have addressed this hypothesis by studying the effect of reconstituting CD43 mutants into the hyperproliferative CD43(-/-) T cells. Reintroduction of full-length CD43 reversed the CD43(-/-) T cell hyperproliferation. Interestingly, despite the lack of exclusion from the interaction site, a mutant containing the CD43 ectodomain on a glycosylphosphatidylinositol linkage was ineffective. Additionally, T cell-APC conjugate formation was not affected by this ectodomain-only construct. In contrast, CD43(-/-) T cell hyperproliferation was reversed by an intracellular-only CD43 fused to the small ectodomain of hCD16. Mutation of this intracellular-only CD43 such that it could not move from the T cell-APC contact site had no further affect on proliferation than the moveable CD43 but did dramatically reduce interleukin-2 production. Thus, the exclusion of the CD43 intracellular region from the immunological synapse is required for CD43 regulation of interleukin-2 production, but the presence of the cytoplasmic tail, independent of its location, is sufficient to reverse CD43(-/-) T cell hyperproliferation.
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PMID:CD43 regulation of T cell activation is not through steric inhibition of T cell-APC interactions but through an intracellular mechanism. 1511 76


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