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

The identification and characterization of regulatory and suppressor T cells that control immune responsiveness to self and non-self antigens has become the focus of innumerable studies. There are two broad categories of naturally occurring and induced CD4(+)CD25(+) regulatory T cells. Naturally occurring T(R) are antigen non-specific and interact directly with other T cells inhibiting their activation. Induced T(R) are either CD4(+)CD25(+) or CD8(+), produce immunosuppressive cytokines such as IL-10, act directly on other T cells or APC and are antigen specific in some but not in all systems. Finally, a distinct subset of T suppressor cells, characterized by their CD8(+)CD28(-) phenotype have been shown to be antigen-specific, recognizing HLA class I/peptide complexes. T(S) act directly on APC inducing the up-regulation of inhibitory receptors ILT3 and ILT4, which render the APC tolerogenic. Tolerized APC, which expresses high ILT3 and ILT4, trigger the generation of antigen-specific CD4(+) T(R) propagating antigen-specific suppression. Up-regulation of ILT3 and ILT4 appears to be a general characteristic of tolerogenic DC since it is also induced by use of vit D3, IL-10 and/or IFN-alpha. The clinical relevance of these inhibitory receptors is in the maintenance of transplantation tolerance as well as in progression of AIDS has been demonstrated.
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PMID:Generation and function of antigen-specific suppressor and regulatory T cells. 1296 77

Several classes of anergic T cells are capable of suppressing naive T cell proliferation and thereby limiting immune responses. Activated T cells, although not anergic, are transiently refractory to restimulation with Ag. We examine in this study whether activated refractory murine T cells can also suppress naive T cell responses. We find that they can, and that they exhibit many of the suppressive properties of anergic T cells. The activated cells strongly diminish Ag-mediated T cell proliferation, an activity that correlates with their refractory period. Suppression is independent of APC numbers and requires cell contact or proximity. Naive T cells stimulated in the presence of activated refractory cells up-regulate CD25 and CD69, but fail to produce IL-2. The addition of IL-2 to culture medium, however, does not prevent the suppression, which is therefore not solely due to the absence of this growth factor. Persistence of the suppressor cells is also not essential. T cells stimulated in their presence and then isolated from them and cultured do not divide. The suppressive cells, however, do not confer a refractory or anergic state on the target T lymphocytes, which can fully respond to antigenic stimulation if removed from the suppressors. Our results therefore provide evidence that activated T cells act as transient suppressor cells, severely constraining bystander T cell stimulation and thereby restricting their response. These results have potentially broad implications for the development and regulation of immune responses.
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PMID:Antigen nonspecific suppression of T cell responses by activated stimulation-refractory CD4+ T cells. 1476 92

Although several observations show local T cell recognition of retinal Ag, there has been no direct demonstration that the APC were retinal derived, rather than recruited. In this study, CD45(+) cells isolated from immunologically quiescent murine retina were tested in vitro for functional evidence of Ag presentation to naive and Ag-experienced CD4 T cells specific for beta-galactosidase. Because CD45(+) cells from brain have been reported to be efficient APC, they were included for comparison. Measures of activation included changes in CD4, CD25, CD44, CD45RB, CD62L, CD69, caspase-3 activation, CFSE dilution, size, number of cells recovered, and cytokine production. Retinal CD45(+) cells gave no evidence of Ag-dependent TCR ligation in naive T cells, unlike splenic APC and CD45(+) cells from brain, which supported potent responses. Instead, addition of retinal CD45(+) cells to cocultures of naive 3E9 T cells plus splenic APC reduced the yield of activated T cells and cytokine production by limiting T cell activation at early time points. Ag-experienced T cells responded weakly to Ag presented by retinal CD45(+) cells. Activating the retinal cells with IFN-gamma, anti-CD40, or LPS incrementally increased their APC activity. Addition of neutralizing Abs to TGF-beta did not reveal suppressed retinal APC activity. Because retina lacks tissue equivalents of meninges and choroid plexus, rich sources of dendritic cells in brain, cells from retina may better represent the APC activity of fresh, adult CNS parenchymal and perivascular cells. The activity of the retinal CD45(+) cells appears to be directed to limiting T cell responses.
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PMID:The antigen-presenting activity of fresh, adult parenchymal microglia and perivascular cells from retina. 1515 73

Aging is associated with a decline in immune function, particularly within the T cell compartment. Because CD8(+) T cells are critical mediators of protective immunity against cancer, which arises more frequently with advancing age, it is important to understand how aging affects T cell-based antitumor responses. We used our DUC18 T cell/CMS5 tumor model system to examine the ability of both aged APCs and aged, tumor-specific CD8(+) T cells to mount protective responses to tumors in vivo. An assessment of aged DUC18 T cells in vitro showed a naive phenotype, but impaired proliferation in response to anti-CD3 and anti-CD28 stimulation. We found that DCs from young and old recipient mice are comparable phenotypically, and endogenous APCs in these mice are equally able to prime adoptively transferred young DUC18 T cells. Even when aged DUC18 T cells are transferred into aged CMS5-challenged mice, Ag-specific proliferation and CD25 expression are similar to those found when young DUC18 T cells are transferred into young mice. Although trafficking to tumor sites appears unequal, old and young DUC18 T cells reject primary CMS5 challenges to the same degree and with similar kinetics. Overall, we found no loss of endogenous APC function or intrinsic defects in CD8(+) DUC18 T cells with advanced age. Therefore, when young and old tumor-specific T cell populations are equivalently sized, CD8(+) T cell-mediated antitumor immunity in our system is not impaired by age, a finding that has positive implications for T cell-based immunotherapies.
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PMID:No intrinsic deficiencies in CD8+ T cell-mediated antitumor immunity with aging. 1524 Jun 70

T suppressor and regulatory cells have been shown to play an important role in the maintenance of central and peripheral tolerance thereby preventing allograft rejection, autoimmunity and allergy. We have previously described a distinct population of antigen-specific CD8(+)CD28(-) T suppressor cells (T(S)). These CD8(+)CD28(-) T(S) cells can be generated in vitro after multiple rounds of stimulation of human peripheral blood mononuclear cells (PBMCs) with either allogenic- or xenogeneic-donor APCs. CD8(+)CD28(-) T(S) cells are FOXP3+, MHC class I-restricted and tolerize both professional antigen presenting cells, such as dendritic cells (DC) and nonprofessional APC such as endothelial cells (EC) by up-regulating the cell surface expression of inhibitory receptors immunoglobulin-like transcript (ILT)-3 and ILT4 and down-regulating the expression of costimulatory molecules such as CD58 and CD86. Tolerized ILT3(high), ILT4(high) APC anergize CD4(+) T(H) cells and can induce the generation of antigen-specific CD4(+)CD25(+) T regulatory cells (T(R)) cells and CD8(+)CD28(-) T(S) cells. In this review, we present our recent studies on the molecular characterization of these antigen specific T suppressor cells and tolerogenic APC.
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PMID:Molecular characterization of allospecific T suppressor and tolerogenic dendritic cells: review. 1558 54

We tested the hypothesis that immature APC, whose NF-kappaB-signaling pathway and thus maturation was blocked by the proteosome inhibitor benzyloxycarbonyl-isoleucyl-glutamyl(O-tert-butyl)-alanyl-leucinal (PSI), could be a source of Ag-specific regulatory T (Treg) cells. DO11.10 CD4(+) T cells that were incubated with Ag- and PSI-pulsed APC proliferated poorly, produced less IL-2, IFN-gamma, and IL-10 in secondary cultures, and inhibited the response of both naive and memory CD4(+) T cells stimulated by Ag-pulsed APC. The generation of PSI-APC Treg cells required IL-10 production by APC. PSI-APC Treg cell inhibition required cell-cell contact but not IL-10 or TGF-beta. Addition of IL-2 did not reverse, but Ab to CTLA-4 did reverse partially the inhibitory effect. Depletion of CD25(+) T cells before initial culture with PSI-APC did not affect Treg generation. PSI-APC Treg cells expressed high levels of Foxp3, inhibited proliferation of naive DO11.10 T cells in vivo, and abrogated colitis driven by a memory Th1 response to bacterial-associated Ag. We conclude that NF-kappaB-blocked, immature APC are able to induce the differentiation of Treg cells that can function in vitro and in vivo in an Ag-specific manner.
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PMID:Generation of antigen-specific, Foxp3-expressing CD4+ regulatory T cells by inhibition of APC proteosome function. 1572 88

Although IL-10 acts as an inhibitory cytokine for APC and CD4(+) T cell function, its effects on CD8(+) T cells are unclear. Additionally, little is known about whether initial priming in the presence of IL-10 can have long-lasting effects and influence subsequent CD8(+) T cell responses that occur in the absence of the cytokine. In the present study, we clarified the role of IL-10 during primary responses and examined whether exposure to IL-10 during initial priming of CD8(+) T cells impacted secondary responses. To determine the effect of IL-10 on Ag-specific T cell responses, peptide-pulsed IL-10R2(-/-) splenic dendritic cells were used to prime T cells from OT-I CD8(+) TCR transgenic mice. During the primary response, the presence of IL-10 resulted in enhancement of CD8(+) T cell numbers without detectable alterations in the kinetics or percentage of cells that underwent proliferation. A modest increase in survival, not attributable to Bcl-2 or Bcl-x(L), was also observed with IL-10 treatment. Other parameters of CD8(+) T cell function, including IL-2, IFN-gamma, TNF-alpha, and granzyme production, were unaltered. In contrast, initial exposure to IL-10 during the primary response resulted in decreased OT-I expansion during secondary stimulation. This was accompanied by lowered IL-2 levels and reduced percentages of proliferating BrdU(+) cells and OT-I cells that were CD25(high). IFN-gamma, TNF-alpha, and granzyme production were unaltered. These data suggest that initial exposure of CD8(+) T cells to IL-10 may be temporarily stimulatory; however, programming of the cells may be altered, resulting in diminished overall responses.
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PMID:Priming in the presence of IL-10 results in direct enhancement of CD8+ T cell primary responses and inhibition of secondary responses. 1584 36

Naturally occurring CD4(+)CD25(+) regulatory T (T(R)) cells, a component of the innate immune response, which play a key role in the maintenance of self-tolerance, have become the focus of numerous studies over the last decade. These cells inhibit the immune response in an Ag-nonspecific manner, interacting with other T cells. Much less is known about adaptive T(R) cells, which develop in response to chronic antigenic stimulation, and act directly on professional and nonprofessional APC, rendering them tolerogenic and able to elicit the differentiation of CD8(+) and CD4(+) T cells with suppressive activity. In this review, we will discuss data pertaining to the bidirectional interaction between Ag-specific T(R) with APC and their clinical relevance.
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PMID:License to heal: bidirectional interaction of antigen-specific regulatory T cells and tolerogenic APC. 1587 80

The sizes of peripheral T cell pools are regulated by competition for environmental signals within a given ecological T cell niche. Cytokines and MHC molecules have been identified as resources for which naive T cells compete to proliferate homeostatically in lymphopenic hosts to fill up their respective compartments. However, it still remains unclear to what extent CD4 and CD8 T cells intercompete for these resources and which role dendritic cells (DC) play in this scenario. Using transgenic mice in which only DC express MHC class I, we demonstrate that this type of APC is sufficient to trigger complete homeostatic proliferation of CD8 T cells in vivo. However, normal numbers of endogenous naive CD4 T cells, but not CD25(+)CD4(+) T regulatory cells, efficiently suppress this expansion in vivo. These findings identify DC as a major resource and a possible target for homeostatic competition between naive CD4 and CD8 T cells.
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PMID:MHC class I-positive dendritic cells (DC) control CD8 T cell homeostasis in vivo: T cell lymphopenia as a prerequisite for DC-mediated homeostatic proliferation of naive CD8 T cells. 1597 49

Although it has been shown that CD4(+)CD25(+) regulatory T cells (T(reg)) contribute to long-term graft acceptance, their impact on the effector compartment and the mechanism by which they exert suppression in vivo remain unresolved. Using a CD4(+) TCR transgenic model for graft tolerance, we have unveiled the independent contributions of anergy and active suppression to the fate of immune and tolerant alloreactive T cells in vivo. First, it is shown that anti-CD154-induced tolerance resulted in the abortive expansion of the alloreactive, effector T cell pool. Second, commensurate with reduced expansion, there was a loss of cytokine production, activation marker expression, and absence of memory T cell markers. All these parameters defined the tolerant alloreactive T cells and correlated with the inability to mediate graft rejection. Third, the tolerant alloreactive T cell phenotype that is induced by CD154 was reversed by the in vivo depletion of T(reg). Reversal of the tolerant phenotype was followed by rapid rejection of the allograft. Fourth, in addition to T(reg) depletion, costimulation of the tolerant alloreactive T cells or activation of the APC compartment also reverted alloreactive T cell tolerance and restored an activated phenotype. Finally, it is shown that the suppression is long-lived, and in the absence of anti-CD154 and donor-specific transfusion, these T(reg) can chronically suppress effector cell responses, allowing long-lived graft acceptance.
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PMID:Analysis of the underlying cellular mechanisms of anti-CD154-induced graft tolerance: the interplay of clonal anergy and immune regulation. 1600 73


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