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

T cell suppression exerted by regulatory T cells represents a well-established phenomenon, but the mechanisms involved are still a matter of debate. Recent data suggest that anergic T cells can suppress responder T cell activation by inhibiting Ag presentation by dendritic cells (DC). In this study, we focused our attention on the mechanisms that regulate the susceptibility of DC to suppressive signals and analyzed the fate of DC and responder T cells. To address this issue, we have cocultured human alloreactive or Ag-specific CD4+ T cell clones, rendered anergic by incubation with immobilized anti-CD3 Ab, with autologous DC and responder T cells. We show that anergic T cells affect either Ag-presenting functions or survival of DC, depending whether immature or mature DC are used as APC. Indeed, MHC and costimulatory molecule expression on immature DC activated by responder T cells is inhibited, while apoptotic programs are induced in mature DC and in turn in responder T cells. Ligation of CD95 by CD95L expressed on anergic T cells in the absence of CD40-CD40L (CD154) interaction are critical parameters in eliciting apoptosis in both DC and responder T cells. In conclusion, these findings indicate that the defective activation of CD40 on DC by CD95L+ CD154-defective anergic T cells could be the primary event in determining T cell suppression and support the role of CD40 signaling in regulating both conditioning and survival of DC.
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PMID:Human anergic CD4+ T cells can act as suppressor cells by affecting autologous dendritic cell conditioning and survival. 1180 39

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-gamma/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27(Kip1) nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G(1) arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.
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PMID:Death ligand TRAIL induces no apoptosis but inhibits activation of human (auto)antigen-specific T cells. 1199 37

Several in vitro and animal studies have been performed to modulate the interaction of APCs and T cells by Fas (CD95/Apo-1) signaling to delete activated T cells in an Ag-specific manner. However, due to the difficulties in vector generation and low transduction frequencies, similar studies with primary human APC are still lacking. To evaluate whether Fas ligand (FasL/CD95L) expressing killer APC could be generated from primary human APC, monocyte-derived dendritic cells (DC) were transduced using the inducible Cre/Loxp adenovirus vector system. Combined transduction of DC by AdLoxpFasL and AxCANCre, but not single transduction with these vectors, resulted in dose- and time-dependent expression of FasL in >70% of mature DC (mDC), whereas <20% of immature DC (iDC) expressed FasL. In addition, transduction by AdLoxpFasL and AxCANCre induced apoptosis in >80% of iDC, whereas FasL-expressing mDC were protected from FasL/Fas (CD95/Apo-1)-mediated apoptosis despite coexpression of Fas. FasL-expressing mDC eliminated Fas(+) Jurkat T cells as well as activated primary T cells by apoptosis, whereas nonactivated primary T cells were not deleted. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC and cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. Induction of apoptosis in Fas(+) target cells required expression of FasL in DC, cell-to-cell contact between effector and target cell, and was not dependent on soluble FasL. The present results demonstrate that FasL-expressing killer APC can be generated from human monocyte-derived mDC using adenoviral gene transfer. Our results support the strategy to use killer APCs as immunomodulatory cells for the treatment of autoimmune disease and allograft rejection.
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PMID:Mature but not immature Fas ligand (CD95L)-transduced human monocyte-derived dendritic cells are protected from Fas-mediated apoptosis and can be used as killer APC. 1275 15

T cell suppression is a well established phenomenon, but the mechanisms involved are still a matter of debate. Mouse anergic T cells were shown to suppress responder T cell activation by inhibiting the antigen presenting function of DC. In the present work we studied the effects of co-culturing human anergic CD4+ T cells with autologous dendritic cells (DC) at different stages of maturation. Either DC maturation or survival, depending on whether immature or mature DC where used as APC, was impaired in the presence of anergic cells. Indeed, MHC and costimulatory molecule up-regulation was inhibited in immature DC, whereas apoptotic phenomena were favored in mature DC and consequently in responder T cells. Defective ligation of CD40 by CD40L (CD154) was responsible for CD95-mediated and spontaneous apoptosis of DC as well as for a failure of their maturation process. These findings indicate that lack of activation of CD40 on DC by CD40L-defective anergic cells might be the primary event involved in T cell suppression and support the role of CD40 signaling in regulating both activation and survival of DC.
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PMID:Both maturation and survival of human dendritic cells are impaired in the presence of anergic/suppressor T cells. 1457 59

Microorganisms with pathogen-associated molecular patterns (PAMP) activate B cells directly by binding to TLR and also indirectly by inducing APC to release cytokines such as BAFF that promote B cell survival. We found that murine B cells activated concomitantly with LPS (TLR-4 ligand) and BAFF are protected from spontaneous apoptosis, but are more susceptible to Fas/CD95-mediated cell death. This increased susceptibility to Fas-induced apoptosis is associated with a dramatic coordinated up-regulation of Fas/CD95 and IRF-4 expression through a mechanism mediated, at least in part, by inhibition of the MEK/ERK pathway. Up-regulation of Fas/CD95 by BAFF is restricted to B cells activated through TLR-4, but not through TLR-9, BCR or CD40. TLR ligands differ in the BAFF family receptors (R) they induce on B cells: BAFF-R is increased by the TLR4 ligand, LPS, but not by the TLR9 ligand, CpG-containing oligodeoxynucleotides, which, in contrast, strongly up-regulates transmembrane activator and CAML interactor (TACI). This suggests the up-regulation of Fas by BAFF is mediated by BAFF-R and not by TACI. Consistently, APRIL, which binds to TACI and B cell maturation antigen but not BAFF-R, did not enhance Fas expression on LPS-activated B cells. Increased susceptibility to Fas-mediated killing of B cells activated with LPS and BAFF may be a fail-safe mechanism to avoid overexpansion of nonspecific or autoreactive B cells.
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PMID:BAFF and LPS cooperate to induce B cells to become susceptible to CD95/Fas-mediated cell death. 1735 8

The diagnosis of classical Hodgkin lymphoma (CHL) has been made in tissue sections as attempts to identify neoplastic Hodgkin and Reed Sternberg (HRS) cells in lymph nodes by flow cytometry (FC) have been unsuccessful. However, we have recently demonstrated that HRS cells can be identified by FC, often present as T-cell-HRS-cell rosettes. In this study, we examined the usefulness of a novel 9-color (CD95-Pacific blue/CD64-fluorescein isothiocyanate/CD30-phycoerythrin [PE]/CD45-PE-Texas red/CD40-PE cyanine [Cy]5.5/CD20-PECy7/CD15-allophycocyanin [APC]/CD71-APC-AlexaFluor A700/CD5-APC-Cy7), single tube FC assay to diagnose CHL in lymph nodes. We used the FC assay to determine diagnostic sensitivity and specificity in 279 blindly identified and 141 selected (for specimen type or cytopreparation morphologic features suggesting CHL) tissues. Of the 53 morphologically defined CHL cases identified (10 in the unselected group; 43 in the selected group), the FC assay diagnostic sensitivity and specificity were 88.7% and 100%, respectively. With the current availability of 8 (or more) color clinical flow cytometers, this assay can now be applied to routinely immunophenotype and confirm a diagnosis of CHL or as an adjunct to immunohistochemical analysis.
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PMID:Flow cytometry can diagnose classical hodgkin lymphoma in lymph nodes with high sensitivity and specificity. 1922 36

The immune system has developed several regulatory mechanisms to maintain homeostasis of adaptive immune responses. T-cell programmed death (PD)-1 recognition of B7-H1 (PD-L1) expressed on APC and non-lymphoid tissue regulates T-cell activation. We show that B7-H1(-/-) mice exhibit exacerbated proteoglycan (PG)-induced arthritis and increased Th-1 CD4(+) T-cell responses. Unexpectedly, the PG-specific antibody response in B7-H1(-/-) mice was diminished. A reduction in the number of peanut agglutinin(+) GC coincided with a decrease in CD19(+) GL-7(+) CD95(+) GC B cells that was a result of increased caspase-induced apoptosis. The percent of CD38(+) CD138(+) emerging plasma cells was decreased. B7-H1(-/-) mice exhibited an increased frequency of CD4(+) PD-1(hi) CXCR5(hi) ICOS(hi) CD62L(lo) T follicular helper cells that displayed a hyperactive phenotype with increased expression of mRNA transcripts for Bcl6, IL-21, and the apoptosis-inducer molecule FasL. In cell transfer of B7-H1(-/-) cells into SCID mice, non-B and non-T cells were sufficient to normalize the antibody response, T-cell hyperactivity, and the development of PG-induced arthritis. These findings indicate that B7-H1 on non-B and non-T cells signals through PD-1 on T effector cells to prevent excessive activation and reduce autoimmune arthritis. Furthermore, these findings demonstrate a novel role for B7-H1 expression in promoting B-cell survival by regulating the activation of T follicular helper cell.
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PMID:B7-H1 expression on non-B and non-T cells promotes distinct effects on T- and B-cell responses in autoimmune arthritis. 2106 40


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