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

Since mouse keratinocytes are tolerogenic antigen presenting cells for T cell activation, the expression of second signal molecules such as B7-1 was targeted to epidermal keratinocytes (KC) in vivo in transgenic mice. The expression vector used to create transgenic mice consisted of a keratin 14 promoter fused 5' to the full length open reading frame of the cDNA encoding mouse B7-1 (between 10 and 30 copies of the transgene per genome). Expression of B7-1 cell surface protein was assessed by in situ immunostaining of cryostat sections of tail skin with CTLA-4/Ig fusion protein, revealing high levels of cell surface expression of B7 by all epidermal KC of transgenic mice, and a lack of such expression in nontransgenic animals. The skin of such transgenic mice (derived from three different founder mice) was grossly and histologically normal, with normal numbers of Langerhans cells and dendritic epidermal T cells. Immunologic challenge of transgenic mice with epicutaneous haptens such as fluorescein isothiocyanate revealed enhanced and persistent delayed-type hypersensitivity responses, with an altered kinetics of resolution when compared with nontransgenic controls. These data indicate that in normal, nontransgenic mice, tolerogenic antigen presentation by KC plays an important physiologic role in damping T cell-mediated inflammation in the skin by competing with professional APC for TCR occupancy in antigen specific T-lymphocytes that migrate into the epidermis. This also implies that altered regulation of B7-1 gene expression by epidermal cells may account for skin "hyperresponsiveness" encountered in some chronic dermatologic disorders.
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PMID:Exaggerated and persistent cutaneous delayed-type hypersensitivity in transgenic mice whose epidermal keratinocytes constitutively express B7-1 antigen. 751 45

The interaction of the T cell surface protein CD28 with its ligand, B7-1 or B7-2, provides a critical costimulatory signal for T cell activation. T cells from CD28- mice are deficient in a variety of responses, including those to lectins and allogeneic spleen cells. However, some immune responses do occur in CD28- mice, suggesting the existence of alternate costimulatory pathways. In this work, we show that T cells purified from CD28- mice respond to B lymphomas expressing 4-1BB ligand (4-1BBL), a member of the TNF gene family. This response is inhibited by a soluble form of 4-1BB, the T cell surface receptor for 4-1BBL. Thus, 4-1BBL/4-1BB interaction provides costimulatory signals to T cells independent of signaling through the CD28 receptor. We find that 4-1BBL is inducible on splenic B cells by CD40 ligand/CD40 interaction or by culturing of splenic dendritic cells, treatments that also induce B7 family molecules. CD28- T cells fail to respond in an MLR to resting allogeneic spleen cells. However, treatment of spleen cells with CD40 ligand renders them competent in activation of CD28- T cells. In contrast to results using B lymphomas as APC, soluble 4-1BB fails to inhibit the T cell response to activated spleen cells. This failure of soluble 4-1BB to block an MLR between CD28+ or CD28- T cells and allogeneic spleen cells is in contrast to a previous report with CD28+ cells.
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PMID:Costimulation of CD28- T lymphocytes by 4-1BB ligand. 899 67

Positive selection of developing thymocytes is associated with changes in cell function, at least in part caused by alterations in expression of cell surface proteins. Surprisingly, however, few such proteins have been identified. We have analyzed the pattern of gene expression during the early stages of murine thymocyte differentiation. These studies led to identification of a cell surface protein that is a useful marker of positive selection and is a likely regulator of mature lymphocyte and APC function. The protein is a member of the Ig superfamily and contains conserved tyrosine-based signaling motifs. The gene encoding this protein was independently isolated recently and termed B and T lymphocyte attenuator (Btla). We describe in this study anti-BTLA mAbs that demonstrate that the protein is expressed in the bone marrow and thymus on developing B and T cells, respectively. BTLA is also expressed by all mature lymphocytes, splenic macrophages, and mature, but not immature bone marrow-derived dendritic cells. Although mice deficient in BTLA do not show lymphocyte developmental defects, T cells from these animals are hyperresponsive to anti-CD3 Ab stimulation. Conversely, anti-BTLA Ab can inhibit T cell activation. These results implicate BTLA as a negative regulator of the activation and/or function of various hemopoietic cell types.
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PMID:An inhibitory Ig superfamily protein expressed by lymphocytes and APCs is also an early marker of thymocyte positive selection. 1512 74

T cell activation can be profoundly altered by coinhibitory and costimulatory molecules. B and T lymphocyte attenuator (BTLA) is a recently identified inhibitory Ig superfamily cell surface protein found on lymphocytes and APC. In this study we analyze the effects of an agonistic anti-BTLA mAb, PK18, on TCR-mediated T cell activation. Unlike many other allele-specific anti-BTLA mAb we have generated, PK18 inhibits anti-CD3-mediated CD4+ T cell proliferation. This inhibition is not dependent on regulatory T cells, nor does the Ab induce apoptosis. Inhibition of T cell proliferation correlates with a profound reduction in IL-2 secretion, although this is not the sole cause of the block of cell proliferation. In contrast, PK18 has no effect on induction of the early activation marker CD69. PK18 also significantly inhibits, but does not ablate, IL-2 secretion in the presence of costimulation as well as reduces T cell proliferation under limiting conditions of activation in the presence of costimulation. Similarly, PK18 inhibits Ag-specific T cell responses in culture. Interestingly, PK18 is capable of delivering an inhibitory signal as late as 16 h after the initiation of T cell activation. CD8+ T cells are significantly less sensitive to the inhibitory effects of PK18. Overall, BTLA adds to the growing list of cell surface proteins that are potential targets to down-modulate T cell function.
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PMID:Functional analysis of B and T lymphocyte attenuator engagement on CD4+ and CD8+ T cells. 1627 94

Members of the TNFR family play critical roles in the regulation of the immune system. One member of the family critical for efficient activation of T-dependent humoral immune responses is CD40, a cell surface protein expressed by B cells and other APC. The cytoplasmic domain of CD40 interacts with several members of the TNFR-associated factor (TRAF) family, which link CD40 to intracellular signaling pathways. TRAF2 and 6 appear to play particularly important roles in CD40 signaling. Previous studies suggest that the two molecules have certain overlapping roles in signaling, but that unique roles for each molecule also exist. To better define the roles of TRAF2 and TRAF6 in CD40 signaling, we used somatic cell gene targeting to generate TRAF-deficient mouse B cell lines. A20.2J cells deficient in TRAF6 exhibit marked defects in CD40-mediated JNK activation and the up-regulation of CD80. Our previous experiments with TRAF2-deficient B cell lines suggest that TRAF6 and TRAF2 may have redundant roles in CD40-mediated NF-kappaB activation. Consistent with this hypothesis, we found CD40-mediated activation of NF-kappaB intact in TRAF6-deficient cells and defective in cells lacking both TRAF2 and TRAF6. Interestingly, we found that TRAF6 mutants defective in CD40 binding were able to restore CD40-mediated JNK activation and CD80 up-regulation in TRAF6-deficient cells, indicating that TRAF6 may be able to contribute to certain CD40 signals without directly binding CD40.
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PMID:A novel mechanism for TNFR-associated factor 6-dependent CD40 signaling. 1787 62

Emerging evidence indicates that in addition to their well-characterized role in antigen presentation, MHC II molecules transmit signals that induce death of APCs. Appropriately timed APC death is important for prevention of autoimmunity. Though the exact mechanism of MHC II-mediated cell death signaling is unknown, the response appears independent of caspase activation and does not involve Fas-FasL interaction. Here we investigated MHC II structural requirements for mediation of cell death signaling in a murine B cell lymphoma. We found that neither the transmembrane spanning regions nor the cytoplasmic tails of MHC II, which are required for MHC II-mediated cAMP production and PKC activation, are required for the death response. However, mutations in the connecting peptide region of MHC II alpha chain (alphaCP), but not the beta chain (betaCP), resulted in significant impairment of the death response. The alphaCP mutant was also unable to mediate calcium mobilization responses, and did not associate with Igalpha/beta. Knock-down of Igbeta by shRNA eliminated the MHC II-mediated calcium response but not cell death. We propose that MHC II mediates cell death signaling via association with an undefined cell surface protein(s), whose interaction is partially dependent on alphaCP region.
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PMID:MHC class II structural requirements for the association with Igalpha/beta, and signaling of calcium mobilization and cell death. 1819 17