Foxp3 occupancy and regulation of key target genes during T-cell stimulation

Marson, Alexander; Kretschmer, Karsten; Frampton, Garrett M.; Jacobsen, Elizabeth S; Polansky, Julia K.; MacIsaac, Kenzie D.; Levine, Stuart S.; Fraenkel, Ernest; Boehmer, Harald von; Young, Richard A.

doi:10.1038/nature05478

Cited by 638 publications

(603 citation statements)

References 33 publications

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“…Interestingly, the classical Treg markers CD73 and CD103 were selectively expressed by induced CD8 1 Foxp3 1 T cells, underlining that their expression is dependent on TGF-b, RA and/or Foxp3. In line with this, CD8 1 T cells deficient in TGF-b signaling fail to up-regulate CD103 in a GVHD model [39], and Foxp3 has been shown to directly bind the CD103 promoter [40]. However, Foxp3-independent mechanisms can also activate CD103 [3], consistent with the only mildly reduced induction of CD103 expression in stimulated T cells from DEREG Â Rag1 À/À Â OTI Â Sf mice (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 66%

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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Section: Discussionmentioning

confidence: 66%

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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“…For example, whereas TCR stimulation upregulates the expression of ZAP-70 in Tconv cells, it downregulates ZAP-70 expression in Treg cells [33]. Foxp3 binds to the promoter region of ZAP-70 gene [33][34][35] and retroviral expression of Foxp3 in Tconv cells reduces their ZAP-70 expression [33]. It remains to be determined how TCR signaling attenuation at the level of ZAP-70 may contribute to Treg-specific functions.…”

Section: Treg-mediated Suppression Mechanismsmentioning

confidence: 99%

Regulatory T cells in cancer immunotherapy

Nishikawa

Sakaguchi

2014

Current Opinion in Immunology

583

548

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“…Since calcium signaling leads to activation of NFAT transcription factor, CD5 may be involved in regulating the activity of Foxp3 via NFAT. Recent studies have identified several Foxp3 interacting proteins and targets such as NFAT and a cyclic AMP dependent phosphodiesterase among others which will have to be evaluated in our system as possible targets of CD5 regulation (46,47).…”

Section: Discussionmentioning

confidence: 99%

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

et al. 2008

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A subset of CD4 + T cells, the CD4 + CD25 + T reg cells in the lymphoid organs and peripheral blood are known to possess suppressive function. Previous in vitro and in vivo studies have indicated that T cell receptor (TCR) signal is required for development of such 'natural regulatory (T reg ) cells' and for activation of the effector function of CD4 + CD25 + regulatory T cells. CD5 is a cell surface molecule present on all T cells and a subtype of B lymphocytes, the B-1 cells, primarily localized to coelomic cavities, Peyer's patches, tonsils and spleen. CD5 acts as a negative regulator of T cell and B cell signaling via recruitment of SHP-1. Here, we demonstrate that T reg cells obtained from CD5 −/− mice are more potent than those from wild type mice in suppressing the in vitro cell proliferation of anti-CD3 stimulated CD4 + CD25 − responder T cells. This phenomenon was cell contact and GITR dependent. Lack of CD5 expression on T reg cells (from spleen, lymph node and thymus) did not affect the intracellular levels of Foxp3. However, CD5 −/− T reg thymocytes were able to elicit a higher Ca 2+ response to TCR + co-stimulatory signals than the wild type cells. CD5 −/− mice expressed more Foxp3 mRNA in the colon than wild type mice, and additionally, the severity of the DSS-induced colitis in CD5 −/− mice was less than the wild type strain. We suggest that manipulation of CD5 expression or the downstream signaling components of CD4 + CD25 + T reg cells as a potential strategy for therapeutic intervention in cases of auto-immune disorders.

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Foxp3 occupancy and regulation of key target genes during T-cell stimulation

Cited by 638 publications

References 33 publications

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

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

Regulatory T cells in cancer immunotherapy

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg cells

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Foxp3 occupancy and regulation of key target genes during T-cell stimulation

Cited by 638 publications

References 33 publications

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

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

Regulatory T cells in cancer immunotherapy

CD5 plays an inhibitory role in the suppressive function of murine CD4+ CD25+ Treg 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

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