High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells

Manavalan, John S.; Rossi, P; Vlad, George; Piazza, Flavia; Yarilina, Anna; Cortesini, Raffaello; Mancini, Donna; Suciu‐Foca, Nicole

doi:10.1016/s0966-3274(03)00058-3

Cited by 275 publications

(311 citation statements)

References 33 publications

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“…Moreover, a soluble recombinant LILRB4 protein can repress T-cell proliferation [50], suggesting that LILRB4 regulates DC activation or immune responses at the interface between DC and T cells. Recent reports have also shown that LILRB4 on tolerogenic DC contributes to the differentiation of Treg [39]. Although this is still controversial because other groups have demonstrated that LILRB4 on 1, 25-dihydroxyvitamin D 3 -treated tolerogenic DC is dispensable for the induction of Treg [51], our present data showed that the deletion of gp49B on DC does not affect the proliferation of Treg (Fig.…”

Section: Discussionsupporting

confidence: 44%

“…Although several inhibitory Ig-like receptors including LILRB1/B2/B4 and PIR-B contribute by maintaining adequate DC development or functions [8,39,42,43], little is known about their physiological roles. In addition, it should be further investigated whether these inhibitory receptors regulate cellular responses at the interface between DC and T cells.…”

Section: Discussionmentioning

confidence: 99%

“…Recent reports indicated the involvement of putative human relatives of gp49B, LILRB2, and LILRB4, in CD4 1 CD25 1 regulatory T-cell (Treg) priming [39]. Since there were no differences in the antigen uptake, maturation, or cytokine production between gp49B À/À and B6 BMDC ( Fig.…”

Section: Treg-mediated Suppression Of Proliferation Was Not Impairedmentioning

confidence: 92%

“…In addition, the proportions of Tconv and Treg among the splenocytes from gp49B À/À and B6 mice were comparable, as assessed by flow cytometry (data not shown). These findings suggest that augmented T-cell activation by gp49B À/À BMDC does not correlate with the altered strength of Treg-mediated suppressive effect.Exacerbated GVH disease in gp49B À/À mice Recent reports suggested that the close relatives of gp49B on DC, murine PIR-B, and human LILRB, participate in the regulation of GVH disease [23,39]. It is well accepted that the recipient's DC trigger a GVH reaction through interaction with allo-reactive donor CD4 1 and CD8 1 T cells [40].…”

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confidence: 99%

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A novel regulatory role of gp49B on dendritic cells in T‐cell priming

et al. 2008

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Dendritic cells (DC) play pivotal roles in the induction and regulation of both innate and acquired immunity. DC express several cell-surface immune inhibitory receptors. However, little is known about their potential immunoregulatory functions in the context of T-cell activation. Here we report that murine gp49B, a member of the immunoglobulin superfamily, harboring immunoreceptor tyrosine-based inhibitory motifs, is expressed on DC and downregulates cellular activity to prevent the excessive activation of T cells in vitro and in vivo. Bone marrow-derived DC (BMDC) from newly generated gp49B-deficient (gp49B À/À ) mice induced enhanced proliferation and IL-2 release of antigen-specific CD4 1 and CD8 1 T cells compared with BMDC from wild-type mice, in a cell-cell contact manner. The enhanced proliferation by gp49B À/À BMDC was also observed in allogeneic CD4 1 and CD8 1 T cells. Moreover, the transfer of allogeneic BALB/c splenocytes into C57BL/6 gp49B À/À mice induced severe acute graft-versus-host disease with an augmented upregulation of CD86 on CD11c 1 splenic gp49B À/À DC, while transfer of C57BL/6 gp49B À/À splenocytes into BALB/c mice did not, suggesting the exacerbation of the disease was due, at least in part, to augmented activation of recipient gp49B À/À DC. These findings demonstrate a novel regulatory role of gp49B in the function of DC.Key words: Antigen presentation Á Costimulation Á DC Á Regulatory receptor Á Tolerance IntroductionDendritic cells (DC) are professional antigen-presenting cells that recognize a diverse repertoire of antigens and present them to naïve T cells for the induction of acquired immunity [1]. DC are also related to innate immunity by producing cytokines such as both type I and II IFN, or by activating NK cells [2,3]. In addition, recent reports revealed that a subset of DC maintains peripheral tolerance in the steady state [4], showing that DC play a pivotal role in the induction of immune responses including autoimmunity.On the DC surface, a variety of structurally different immunoreceptors that regulate DC and T-cell functions have been found, including CD80, CD86, CD40, and various Ig superfamily and lectin family molecules [5]. Among them, a group of paired Ig superfamily receptors, termed Ig-like receptors, have been attracting the interest of many researchers because they are expressed on various subsets of DC and are considered to contribute to the development or activation of DC [6][7][8][9][10]. Generally, Ig-like receptors are subdivided into two types, namely activating and inhibitory receptors, and in some cases they are expressed on hematopoietic cells in a pair-wise manner [11][12][13][14]. Most activating receptors associate with homodimeric subunits containing ITAM, such as the FcR common g chain and KARAP/DAP12 [15,16], and deliver positive signals into the cells through interaction with their ligands [17]. For instance, the uptake of immune complexes through activating FcR for IgG 2426augments DC maturation, leading to efficient antigen presentation [18...

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Section: Discussionsupporting

confidence: 44%

Section: Discussionmentioning

confidence: 99%

Section: Treg-mediated Suppression Of Proliferation Was Not Impairedmentioning

confidence: 92%

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A novel regulatory role of gp49B on dendritic cells in T‐cell priming

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“…Interestingly, such cells suppressed CD4 + T cells responses and induced regulatory CD4 + CD25 + T cells. Immunoregulation was dependent on the presence of an APC "bridge" between responding CD4 + and CD8 + T cells [8]. IL-10-dependent CD8 + regulatory T cells have been described after type 2 dendritic cell stimulation of peripheral naive CD8 + T cells [9].…”

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Low‐avidity CD8^lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8^hi T cell responses to the same antigen

et al. 2006

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We have previously reported that multiple injections of soluble MHC class I tetramers assembled with wild-type HY peptide induces unresponsiveness to male skin grafts in naive female C57BL/6 (B6) mice. Induction of unresponsiveness is dependent on a population of unresponsive allospecific CD8 lo T cells. Reduced expression of CD8 acts to limit a T cell response to HY peptide by limiting the avidity window of effective signal transduction. We and others have demonstrated that CD8 lo T cells are an alternative stable phenotype of CD8ab + T cells in vitro and in vivo after antigen stimulation. We show here that CD8 lo T cells can suppress naive CD8 + T cell responses to HY antigen in vitro and male skin graft rejection in vivo after adoptive transfer into female recipients. These novel regulatory T cells express surface TGF-b1 and secrete T cytotoxic 2 cytokines after antigen-specific stimulation. Anti-TGF-b antibody and latency-associated peptide inhibit the suppressive effects in vitro. We also show that HY-specific memory CD8 + T cells overcome regulation by CD8 lo T cells. These data define a novel peripheral regulatory CD8 + T cell population that arises after repeated antigen encounter in vivo. These cells have implications in the maintenance of tolerance and memory.See accompanying commentary http://dx.doi.org/10.1002/eji200535797 IntroductionDuring the past few years, mechanisms of regulation of T cell activity have attracted much attention. There has been a resurgence of interest in regulatory T cells in autoimmunity, and more recently, harnessing their potential as a means to prevent graft rejection [1], albeit largely unsuccessful to date. While it is clear that CD4 + CD25 + T cells play a critical role in the control of T cell responses [2,3], studies of CD8 + T cell-mediated regulation have been sparse to date, and have revealed different forms of regulation utilizing both deletional and non-deletional mechanisms [4]. For instance, active immunosuppression by transfusion of donor-specific lymphocytes into a murine TCR transgenic mice induced regulatory TCR + CD4 -CD8 -T cells (double negative T cells, DNTC) population [5]. These T cells induced apoptosis in activated donor-specific CD8 + T cells via a Fas-dependent pathway, but not T cells activated to a third-party alloantigen. It appears that these regulatory T cells require antigen-specific recognition. Indeed, DNTC were found to acquire MHC-allopeptide complexes from APC that were presented on their surface. As a result these DNTC functioned as "killer APC" in conjunction with up-regulated FasL induced by activation [5,6]. In contrast to deletional regulation, a distinct population of CD8 + CD28 -T suppressor (Ts) cells were found to be generated in vitro after multiple rounds of stimulation of human peripheral blood mononuclear cells with allogeneic donor APC or self-APC pulsed with allogeneic peptide [7]. Interestingly, such cells suppressed CD4 + T cells responses and induced regulatory CD4 + CD25 + T cells. Immunoregulation was dependent on th...

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Microbial Instruction of Dendritic Cells

Jong¹,

Smits²,

Wierenga³

et al. 2006

Handbook of Dendritic Cells

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High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells

Cited by 275 publications

References 33 publications

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

Low‐avidity CD8^lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8^hi T cell responses to the same antigen

Microbial Instruction of Dendritic Cells

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High expression of ILT3 and ILT4 is a general feature of tolerogenic dendritic cells

Cited by 275 publications

References 33 publications

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

A novel regulatory role of gp49B on dendritic cells in T‐cell priming

Low‐avidity CD8lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8hi T cell responses to the same antigen

Microbial Instruction of Dendritic Cells

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Product

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Low‐avidity CD8^lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8^hi T cell responses to the same antigen