Distinct Subsets of FoxP3+ Regulatory T Cells Participate in the Control of Immune Responses

Stephens, Geoffrey L.; Andersson, John; Shevach, Ethan M.

doi:10.4049/jimmunol.178.11.6901

Cited by 85 publications

(94 citation statements)

References 46 publications

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“…Notably, naturally occurring CD8 1 Foxp3 1 T cells expressed a CD8-ab heterodimer, TCR-ab, CD3-e (data not shown) and partially CD4 (Supporting Information Fig. 4); the latter consistent with previous reports [2,25]. In summary, CD8 1 Foxp3 1 T cells express classical CD4 1 Foxp3 1 Treg markers in a pattern distinct from activated CD8 1 Foxp3 À T cells and previously described CD8 1 Tregs.…”

Section: Natural and Induced Cd8 1 Foxp3 1 T Cells Express Classical supporting

confidence: 89%

“…Interestingly, a CD8 1 Foxp3 1 population expands in MHCclass-II-deficient mice and shares phenotypic and functional features with CD4 1 CD25 1 Tregs [37], whereas the absence of CD8 1 Foxp3 1 T cells in MHC-class-I-deficient mice suggests MHCI restriction [25]. The presence of Foxp3 1 cells among CD8SP thymocytes suggests at least a partial thymic origin of CD8 1 Foxp3 1 T cells, similar to CD4 1 Foxp3 1 Tregs [18], although re-immigration into the thymus after peripheral conversion cannot be formally excluded.…”

Section: Discussionmentioning

confidence: 99%

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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

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: Natural and Induced Cd8 1 Foxp3 1 T Cells Express Classical supporting

confidence: 89%

Section: Discussionmentioning

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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“…CD103 is a cell surface protein of the integrin family and is proposed as a marker for effector/memory Tregs in mice (3)(4)(5)(6). These CD103 + Tregs are more potent in suppressing harmful inflammatory reactions compared with CD103 2 Tregs in different mouse models of autoimmune diseases and Leishmania infection (3,4,6).…”

Section: R Egulatory T Cells (Tregs) Play An Important Role In the Mamentioning

confidence: 99%

“…CD103 + Tregs accumulate in the tumor microenvironment and express high levels of CCR5 in tumor-bearing mice It was reported that CD103 + Tregs were enriched within lymphoid tissues draining an inflammatory site or an inflammatory site (4,5). We next examined whether CD103 + Tregs could accumulate in the tumor-draining lymph node or in tumors.…”

Section: Tregs In Vitromentioning

confidence: 99%

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The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Chang

Lin

Kang

et al. 2012

The Journal of Immunology

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CD103 is a marker for identification of effector/memory regulatory T cells (Tregs). CD103+ Tregs are potent suppressors of tissue inflammation in several infectious diseases, autoimmune diseases, and cancers. However, the underlying mechanisms for this potent suppression ability remain unclear. The current study was designed to clarify this issue. Unexpectedly, we found both CD103+ and CD103− Tregs had similar suppression capacity in vitro. We then chose a murine tumor model for investigation of the in vivo behavior of these Tregs. The suppression ability in vivo against the anti-tumor ability of CD8+ T cells was restricted to CD103+ Tregs although both Tregs had equal in vitro suppression ability. In addition, CD103+ Tregs expressed significantly higher levels of CCR5 than those of CD103− Tregs and accumulated more in tumors than did CD103− Tregs. Furthermore, blockade of CCR5 signaling, either by CCR5−/−CD103+ Tregs or by CCL5 knockdown tumor, could reduce the migration of CD103+ Tregs into tumors and impair their in vivo suppression ability. In conclusion, these results indicate that the potent in vivo suppression ability of CD103+ Tregs is due to the tissue-migration ability through CCR5 expression.

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Diversification and senescence of Foxp3⁺ regulatory T cells during experimental autoimmune encephalomyelitis

Tauro

Nguyen

et al. 2013

Eur J Immunol

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The fate of Foxp3+ regulatory T cells (Treg) responding during autoimmunity is not well defined. We observed a marked elevation in KLRG1+ CNS-infiltrating Treg in experimental autoimmune encephalomyelitis (EAE), and assessed their origin and properties. KLRG1+ Treg showed increased activation marker expression, Foxp3 and CD25 levels, and more rapid cell cycling than KLRG1− cells. KLRG1− Treg converted into KLRG1+ cells and this was increased in the context of autoimmune inflammation. Conversion was unidirectional; KLRG1+ Treg did not revert to a KLRG1− state. KLRG1+ but not KLRG1− Treg survived poorly, indicative of terminal differentiation. This was associated with diminished BCL2 and increased apoptosis of isolated cells. KLRG1 was not upregulated on iTreg in culture, but was after transfer and EAE induction or on iTreg developing spontaneously during EAE. KLRG1+ Treg produced more IL10 and had altered effector cytokine production compared with KLRG1− Treg. Despite their differences, KLRG1+ and KLRG1− Treg proved similarly potent in suppressing EAE. KLRG1+ and KLRG1− populations were phenotypically heterogeneous, with the extent and pattern of activation marker expression dependent both on cellular location and inflammation. Our results support an extensive diversification of Treg during EAE, and associate KLRG1 with altered Treg function and senescence during autoimmunity.

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Distinct Subsets of FoxP3+ Regulatory T Cells Participate in the Control of Immune Responses

Cited by 85 publications

References 46 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

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Diversification and senescence of Foxp3⁺ regulatory T cells during experimental autoimmune encephalomyelitis

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Distinct Subsets of FoxP3+ Regulatory T Cells Participate in the Control of Immune Responses

Cited by 85 publications

References 46 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

The Indispensable Role of CCR5 for In Vivo Suppressor Function of Tumor-Derived CD103+ Effector/Memory Regulatory T Cells

Diversification and senescence of Foxp3+ regulatory T cells during experimental autoimmune encephalomyelitis

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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

Diversification and senescence of Foxp3⁺ regulatory T cells during experimental autoimmune encephalomyelitis