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

Stimulation of the TCR of activated, mature T cells by an APC produces a spectrum of functional responses. Most of those responses positively promote immunity and inflammation. However, death of the responding T cell, which would limit subsequent inflammation, can also result from such stimulation. We compare the Ag threshold necessary to promote inflammation through cytokine production with the Ag threshold necessary to limit inflammation through T cell death. These two responses are independently regulated by the APC and this regulation is selective for both different APC products and different T cell subsets. The costimulator B7 selectively decreases the Ag threshold for cytokine production in Th1 cells with no effect on the Ag threshold for Th1 death. B7 has no effect on the Th2 Ag threshold for cytokine production or death. In contrast, IFN-gamma negatively modulates a macrophage product that selectively increases the threshold of Ag necessary to stimulate death in Th2 cells, but has no effect on cytokine production by Th2 cells or cytokine production or death of Th1 cells. This selective regulation of cytokine production and T cell death may play an important role in both shaping the quality of a given immune response and in providing a general mechanism for the regulation of the immune response by limiting inflammation and through peripheral deletion of inappropriate T cell specificities.
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PMID:Differential activation of antigen-stimulated suicide and cytokine production pathways in CD4+ T cells is regulated by the antigen-presenting cell. 768 85

The direct effects of IL-10 on the proliferation and lymphokine production of human peripheral blood T cells and CD4+ T cell clones representing the Th0, Th1-like, and Th2-like Th cell subsets were investigated in the absence of professional APC. IL-10 partially inhibited the proliferative responses of CD4+ human T cell clones induced by anti-CD2 or anti-CD3 mAb cross-linked on CD32 (Fc gamma RII)-transfected mouse L cells. Transfection of ICAM-1 or LFA-3 in CD32+ L cells resulted in enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD3 mAb, whereas transfection of B7 in CD32+ L cells enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD2 mAb. In addition, B7 expression on CD32+ L cells was required for activation of small resting T cells by anti-CD3 or anti-CD2 mAb. IL-10 inhibited the proliferation of T cell clones induced by anti-CD2 or anti-CD3 mAb on CD32+ L cells expressing these accessory molecules, indicating that interactions of LFA-3, ICAM-1, and B7 with their ligands on T cells did not overcome the inhibitory effects of IL-10. Inhibition of proliferation of T cell clones by IL-10 was in all instances completely neutralized by relatively low concentrations of IL-2, whereas IL-4 was ineffective. IL-10 did not affect the expression of the TCR/CD3 complex, CD2, LFA-1, CD28, or IL-2R alpha- or beta-chains, nor did it inhibit the induction of the latter two molecules on T cells after activation. Inhibition of proliferation was found to be the result of specific inhibition of IL-2 production by the responding T cell subsets, which occurred at the mRNA level. The production and mRNA levels of IL-4, IL-5, IFN-gamma, and granulocyte/macrophage-CSF were not affected by IL-10. Taken together, these results indicate that IL-10/IL-10R interaction on CD4+ T cell clones and peripheral blood T cells results in signaling pathways that specifically interfere with activation processes leading to IL-2 production. These direct inhibitory effects on IL-2 production by activated T cells may contribute to the general immunosuppressive activities of IL-10.
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PMID:Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. 768 12

Recent work has indicated the significance of IL-4- and IL-5-secreting allergen-specific human Th2 lymphocytes in the control of immune responses to allergens in atopic individuals. The precise allergenic epitopes that activate these allergen-specific Th2 cells are, however, hardly known. We analyzed the epitope-specificity of T lymphocytes specific for Der p II, one of the major allergens of house dust mite Dermatophagoides pteronyssinus. Using a panel of overlapping synthetic peptides that span the entire Der p II molecule, we could demonstrate that polyclonal Der p II-specific T cell lines prepared from the peripheral blood of five atopic patients can react with at least 10 different epitopes of the molecule. Each donor showed a different pattern of reactivity with the synthetic peptides, suggesting that Der p II contains multiple T cell epitopes that may differ from individual to individual. We studied the specificity of the T cell response to Der p II in more detail in one atopic patient using a short term polyclonal T cell line that strongly reacted to one single peptide (116-129) of the allergen. From this patient we established a panel of 11 Der p II-specific TLC. Ten TLC were of the CD3+ CD4+ phenotype and showed a high IL-4/IFN-gamma production ratio, whereas another TLC expressed CD3 and CD8 and failed to secrete substantial IL-4 and IFN-gamma. The use of at least four different TCR V beta gene segments was shown within this panel TLC. All TLC tested recognized the allergen in an HLA-DR1-restricted manner. Although this patient reacted to only one peptide on the polyclonal level, two T cell epitopes were identified on the clonal level by using synthetic peptides and autologous APC to stimulate the TLC. Combining data of CD4/CD8 expression, TCR V beta usage, and epitope specificity, at least six different types of Der p II-specific TLC could be identified within this patient. Binding of IgE to all synthetic peptides of Der p II is low and of low affinity, which may be of particular importance with respect to possible desensitization protocols using such peptides.
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PMID:T cell epitopes of house dust mite major allergen Der p II. 768 99

In the human model, requirements for the primary onset of IFN-gamma and IL-4 production in maturing T helper lymphocytes were compared. Stimulation of freshly isolated CD4+CD45RA+ naive Th cells with immobilized CD3 mAb in the presence of exogenous IL-2 resulted in the proliferative response of this subset, which was equal to or higher than CD4+CD45R0+ memory Th cells. Throughout the first 6 days after this mode of stimulation, naive Th cells did not secrete IL-4 and produced only small amounts of IFN-gamma, whereas high amounts of both lymphokines were secreted by stimulated autologous memory Th cells. Under these conditions, naive Th cells acquired the CD45RA-CD45R0+ memory phenotype. After restimulation, such in vitro-generated CD45R0+ cells produced high amounts of IFN-gamma but, despite the full phenotype conversion, they produced only trace amounts of IL-4. In contrast, when the primary stimulation and the expansion of cells proceeded in the presence of IL-1 beta or CD28 mAb, both IFN-gamma and IL-4 were produced after restimulation, in similar amounts compared with those produced by memory Th cells. The effect of IL-1 beta and CD28 signaling could not be obtained by the administration of exogenous IL-4 nor could the onset of IL-4 production be prevented by the presence of a neutralizing anti-IL-4 Ab in primary cultures. These data show that the development of human IL-4-producing Th cells can proceed in the absence of any pre-existing source of IL-4 and can be driven solely by the APC-related signals.
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PMID:Functional maturation of human naive T helper cells in the absence of accessory cells. Generation of IL-4-producing T helper cells does not require exogenous IL-4. 770 16

The infection of mice with Leishmania major parasite induces polarized Th1 and Th2 responses that cannot be significantly changed in vivo after 2 to 3 wk of infection by using either cytokines or anti-cytokine Abs. It is not clear, however, whether the T cell populations are irreversibly differentiated or whether the inability to modify the cytokine production reflects inefficiencies in the experimental treatments or complications of the infection itself. To study this further, we have cultured CD4+ T cells from L. major-infected mice with specific Ag, APC, and IL-2, in the presence or absence of different cytokines and/or anti-cytokine Abs. Th1 cells cultured for 1 wk in the presence of IL-4 produced very low levels of IFN-gamma but, instead, produced high levels of IL-4 and IL-10, suggesting that IL-4 was able to cause the conversion of a Th1 into a Th2 population. The Th2-like population generated in vitro was stable and retained its phenotype in vivo when transferred into L. major-infected C.B-17 scid mice. In contrast, the presence of IFN-gamma and IL-12 during the Th2 cell stimulation enhanced IFN-gamma production but was not sufficient to induce a complete conversion of a Th2 into a Th1-like population. Taken together, these data show that highly polarized murine Th populations can be modified and even converted to the opposite cytokine phenotype in vitro, suggesting possible therapeutic applications for cytokines.
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PMID:Induction of a Th2 population from a polarized Leishmania-specific Th1 population by in vitro culture with IL-4. 770 19

Although IL-12 is known to enhance IFN-gamma synthesis in unprimed CD4+ T cells, the effect of IL-12 on IL-4 synthesis in primed CD4+ T cells, which are thought to have relatively fixed cytokine profiles, has not been clearly examined. We examined the effects of IL-12 on cytokine production by CD4+ keyhole limpet hemocyanin (KLH)-primed memory lymph node T cells and by already established KLH-specific CD4+ T cell clones. First, we found that the presence of IL-12 greatly reduced the development of IL-4 synthesis in resting but not activated memory CD4+ T cells. Although IL-12 did not inhibit the production of IL-4 in cloned Th2 effector cells, it greatly inhibited the development of IL-4 synthesis in primed CD4+ T cells taken from the lymph nodes of mice previously immunized with KLH. Secondly, we found that IL-12 inhibited IL-4 synthesis either when directly added to cultures of T cells or when APC were preincubated in IL-12. Inasmuch as the enhancing effect of IL-12 on IFN-gamma synthesis occurred optimally only when the T cells were cultured directly in IL-12, these studies indicate that IL-12 affects IL-4 synthesis via a mechanism that involves APC, a process that differs from that by which it affects IFN-gamma synthesis. These studies also indicate that the administration of IL-12 would be clinically useful in treating patients, for example those with allergic disease or lepromatous leprosy, in whom memory T cells inappropriately overproduce IL-4.
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PMID:IL-12 inhibits IL-4 synthesis in keyhole limpet hemocyanin-primed CD4+ T cells through an effect on antigen-presenting cells. 787 34

Although the importance of CD4+ T cells for the induction of an effective CD8+ cytolytic T cell response is well documented, the mechanism by which MHC class II-negative tumor cells recruit CD4+ T help is not well understood. We have previously shown that IL-2 or IFN-gamma gene-modified CMS-5 tumor cells do not grow in syngeneic mice; however, mice which rejected the cytokine-secreting tumor cells develop a protective immune response against a challenge with parental tumor cells. Here we show that rejection of IL-2-secreting CMS-5 cells is not mediated by T cells. However, establishment of a protective immune response against CMS-5 tumor cells requires the presence of both CD4+ and CD8+ T cell subsets during the period of immunization with IL-2-secreting CMS-5 cells as well as during the effector phase. Extensive histologic analysis has failed to detect the presence of T cells at the site of immunization with either IL-2- or IFN-gamma-secreting CMS-5 cells. The main infiltrate at the site of inoculation with IL-2-secreting CMS-5 cells consisted of NK cells that appeared to play a role in their rejection. The predominant infiltrate at the site of inoculation with IFN-gamma-secreting CMS-5 cells consisted of macrophages. These observations argue against a direct role for the intact tumor cell in presenting either T helper or CTL epitopes to the immune system, and support the view that specialized APC are responsible for the in vivo priming of a T cell response against MHC class I-restricted Ag.
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PMID:The role of IL-2 secreted from genetically modified tumor cells in the establishment of antitumor immunity. 790 36

In these experiments, effects of IL-12 on the proliferation and IL-2R expression of Th1 and Th2 clones were studied. Although neither Th1 nor Th2 clones proliferated on an Ag stimulation with B cell APC, Th1 clones but not Th2 clones, exhibited IL-2-dependent proliferation in the presence of IL-12 in response to the Ag stimulation. The IL-2R alpha-chain was also shown to be induced on Th1 clones when they were stimulated with B cell APC in the presence of IL-12. Effects of IL-12 on these T cell functions were indicated to be exerted in concert with IL-2, although IL-12 did not enhance IL-2 production of Th1 clones. Cytokines produced by Th1 clones such as IFN-gamma and TNF-alpha were indicated not to be involved in induction of the IL-2R alpha-chain expression or proliferation. IL-12 also induced proliferation and IL-2R alpha-chain expression of Th1 clone stimulated with anti-CD3 in the absence of APC, indicating that IL-12 exerted the effect on Th1 cells directly and other costimulator signal from APC is not required for the function of IL-12. In contrast to IL-12, IL-1 induced proliferation and IL-2R alpha-chain expression of Th2 clones stimulated with Ag on B cell APC. The failure of IL-12 in the induction of IL-2R alpha-chain expression on Th2 clone seemed not to be caused by the IL-4 produced by the clone. These results suggest that IL-12 plays an important role in IL-2R alpha-chain expression and proliferation of Th1 clones, but not Th2 clones, as a second signal.
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PMID:Second signal activity of IL-12 on the proliferation and IL-2R expression of T helper cell-1 clone. 790 27

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

In this report, we present evidence that the CTL response directed against MHC Class I allo-determinants can be inhibited as a result of IL-10 expression in vivo. The presence of localized IL-10 secretion at the site of allogeneic tumor cell challenge resulted in marked inhibition of the CTL response and allowed growth of the tumor in the allogeneic host. Using purified CD4+ T cells from mice immunized in the presence or absence of IL-10, we have shown that the loss of alloreactivity as a consequence of IL-10 expression results from the inhibition of CD4+ T cell function. The expression of either IL-2 or IFN-gamma with IL-10 locally at the time of allogeneic cell challenge completely restored CTL alloreactivity, suggesting that the action of IL-10 could be bypassed by providing helper T lymphocyte-derived cytokines of the Th1 type at the site of immunization. Inhibition of alloreactivity by IL-10 was observed using either purified macrophages or dendritic cells as APC in an in vitro assay. Thus, the expression of IL-10 following antigenic challenge (such as that observed in Th2-like immune responses) may profoundly limit the ability for generating functional CTL in vivo.
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PMID:IL-10 inhibits alloreactive cytotoxic T lymphocyte generation in vivo. 799 51


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