CD8+CD205+ Splenic Dendritic Cells Are Specialized to Induce Foxp3+ Regulatory T Cells

Yamazaki, Sayuri; Dudziak, Diana; Heidkamp, Gordon F.; Fiorese, Christopher J.; Bonito, Anthony J.; Inaba, Kayo; Nussenzweig, Michel C.; Steinman, Ralph M.

doi:10.4049/jimmunol.181.10.6923

Cited by 366 publications

(397 citation statements)

References 80 publications

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“…1A and B). DEC-205 has been used to identify a population of tolerogenic DC specialized for the induction of Foxp3 1 Treg [27], and for the first time, we showed that a parasite product can increase the surface expression of the CLR DEC-205 directly on T cells. The upregulation of surface expression of galectin-3 is particularly interesting given the recent observation that galectin-3, recruited intracellularly to the immunological synapse, negatively regulates TCR-mediated CD4 1 T-cell activation [28].…”

Section: Discussionmentioning

confidence: 85%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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The immunomodulatory effect of Schistosoma mansoni antigens has often been attributed to interaction with PRR expressed on APC. Our previous work has shown that S. mansonisoluble egg antigen (SEA) can induce, together with a Th2 response, TGF-b-dependent Foxp3 expression in naïve CD4 1 T cells from NOD mice. We found that SEA can directly upregulate the expression of surface-bound TGF-b in purified CD4 1 T cells in the absence of accessory cell interactions. In this study, we show that the C-type lectin receptors DEC-205 and galectin-3 were involved in the direct interaction between S. mansoni antigens and CD4 1 T cells. SEA was able to enhance CD4 1 T-cell secretion of bioactive TGF-b in response to TLR2 ligand stimulation, in the absence of APC. We also show that TLR2 expressed on CD4 1 T cells was important for the Foxp3 expression induced by SEA.

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Section: Discussionmentioning

confidence: 85%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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“…Specialized dendritic cells (DC) can initiate the latter process by providing the key factors TGF-b and all-trans-retinoic acid (RA) [18,19]. Although natural and in vitro induced CD4 1 Foxp3 1 Tregs share key phenotypic and functional characteristics, they differ in the stability of Foxp3 expression, and different degrees of demethylation of an evolutionarily conserved region within the foxp3 locus (TSDR; Treg-specific demethylated region) have been implicated in this observation [20].…”

Section: Introductionmentioning

confidence: 99%

CD8⁺Foxp3⁺ T cells share developmental and phenotypic features with classical CD4⁺Foxp3⁺ regulatory T cells but lack potent suppressive activity

et al. 2011

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''Suppressor T cells'' were historically defined within the CD8 1 T-cell compartment and recent studies have highlighted several naturally occurring CD8 1 Foxp3 À Treg populations. However, the relevance of CD8 1 Foxp3 1 T cells, which represent a minor population in both thymi and secondary lymphoid organs of nonmanipulated mice, remains unclear. We here demonstrate that de novo Foxp3 induction in peripheral CD8 1 Foxp3 À T cells is counter-regulated by DC-mediated co-stimulation via CD80/CD86. CD8 1 Foxp3 1 T cells fail to develop in TCR-transgenic mice with Rag1 À/À background, similar to classical CD4 1 Foxp3 1 Tregs. Notably, both naturally occurring and induced CD8 1 Foxp3 1 T cells express bona fide Treg markers including CD25, GITR, CTLA4 and CD103, and show defective IFN-c production upon restimulation when compared with their CD8 1 Foxp3 À counterparts. However, utilizing DEREG transgenic mice for the isolation of Foxp3 1 cells by eGFP reporter expression, we demonstrate that induced CD8 1 Foxp3 1 T cells similar to activated CD8 1 Foxp3 À T cells only mildly suppress T-cell proliferation and IFN-c production. We therefore categorize CD8 1 Foxp3 1 T cells as a tightly controlled population sharing certain developmental and phenotypic properties with classical CD4 1 Foxp3 1 Tregs, but lacking potent suppressive activity.Keywords: CD8 . Foxp3 . TGF-b . Treg Supporting Information available online IntroductionFoxp3 is a master regulator of CD4 1 Treg function [1][2][3] and its mutation or the depletion of Foxp3 1 cells led to onset of multiorgan autoimmunity [4][5][6]. The vast majority of Foxp3 1 T cells are confined to TCR-ab 1 CD4 1 T cells, and little is known about CD8 1 T cells expressing Foxp3. Certain surface phenotypes such as CD28 À [7], CD122 1 [8], CD8aa 1 [9, 10], latencyassociated peptide (LAP) 1 [11] and restriction to the nonclassical MHCI molecule Qa-1 [12] have been linked with immunosuppressive functions of CD8 1 T cells. However, Foxp3 expression was either absent in these populations [8,9,[13][14][15] 716with the defining surface phenotype [11] or was not investigated specifically on a protein level [16]. Additionally, the isolation of viable CD8 1 Foxp3 1 populations was hampered by the nuclear localization of Foxp3 in conjunction with the occurrence of these cells at low numbers in nonmanipulated mice [2,17], rendering the identity and relevance of mouse CD8 1 Foxp3 1 T cells unclear.Classical CD4 1 Foxp3 1 Tregs develop either intrathymically (natural Tregs, nTregs) or in the periphery via conversion from Foxp3 À T cells (induced Tregs). Specialized dendritic cells (DC) can initiate the latter process by providing the key factors TGF-b and all-trans-retinoic acid (RA) [18,19]. Although natural and in vitro induced CD4 1 Foxp3 1 Tregs share key phenotypic and functional characteristics, they differ in the stability of Foxp3 expression, and different degrees of demethylation of an evolutionarily conserved region within the foxp3 locus (TSDR; Treg-specific demethylated region) have b...

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“…14,15 Some dendritic cells (DCs), such as immature DCs (imDCs) and plasmacytoid DCs, exhibit regulatory but not stimulatory functions on CD4 1 T cells. [16][17][18][19] Therefore, these DCs, especially monocyte-derived imDCs, have been used to induce antigen-specific CD4 1 Tregs from naive precursors.…”

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confidence: 99%

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

et al. 2010

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CD4 1 regulatory T cells (Tregs) play an important role in maintaining immune tolerance by suppressing pathologic immune responses. The generation of large numbers of antigen-specific Tregs ex vivo is critical for the development of clinical immunotherapy based on the adoptive transfer of Tregs. Both CD40-activated B cells (CD40-B) and immature dendritic cells (imDCs) have been used as professional antigen-presenting cells (APCs) to generate antigen-specific Tregs. However, the efficiencies of CD40-B and imDCs to generate CD4 1 Tregs have not been compared directly and the mechanism driving the generation of these Tregs remains largely unknown. In this study, we found that CD40-B exhibited mature phenotypes and were more able to induce and expand CD4 high CD25 1 Tregs than imDCs. Moreover, Tregs induced by CD40-B had greater suppressive capacity than those induced by imDCs. The generation of CD4 high CD25 1 Tregs by CD40-B and imDCs is cell-cell contact dependent and partially relies on the expression of human leukocyte antigen (HLA)-DR and CD80/86. Differences in CD4 high CD25 1 Treg generation efficiency were largely explained by the production of endogenous IL-2 by CD40-B. Our results suggest that CD40-B is better able to generate large numbers of antigen-specific Tregs than imDCs. Additionally, using CD40-B to generate Tregs may accelerate the clinical use of Treg-based immunotherapy in the treatment of allograft rejection, graft versus host disease (GVHD) and autoimmune diseases.

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CD8+CD205+ Splenic Dendritic Cells Are Specialized to Induce Foxp3+ Regulatory T Cells

Cited by 366 publications

References 80 publications

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

CD8⁺Foxp3⁺ T cells share developmental and phenotypic features with classical CD4⁺Foxp3⁺ regulatory T cells but lack potent suppressive activity

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

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CD8+CD205+ Splenic Dendritic Cells Are Specialized to Induce Foxp3+ Regulatory T Cells

Cited by 366 publications

References 80 publications

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4+ regulatory T cells

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CD8⁺Foxp3⁺ T cells share developmental and phenotypic features with classical CD4⁺Foxp3⁺ regulatory T cells but lack potent suppressive activity