Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control

Wirnsberger, Gerald; Mair, Florian; Klein, Ludger

doi:10.1073/pnas.0901877106

Cited by 93 publications

(105 citation statements)

References 30 publications

(36 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1C). We observed that CD8SP thymocytes up-regulated Foxp3 more efficiently than CD8 1 T cells from peripheral sources which might relate to a T-cell intrinsic capability of immature T cells for Foxp3 induction as previously observed for CD4 1 T cells [28,29]. Although CD80/ CD86 was reported to be essential for the generation of CD4 1 Foxp3 1 Tregs in vivo [30], DC actively repressed Foxp3 induction in part via CD80/CD86-mediated co-stimulation in vitro.…”

Section: Discussionsupporting

confidence: 78%

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

et al. 2011

View full text Add to dashboard Cite

''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...

show abstract

Section: Discussionsupporting

confidence: 78%

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

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Hence, thymocytes from newborns were more readily differentiated into Tregs than thymocytes from adults (35). Moreover, thymic APCs were shown to be more potent at sustaining thymocyte than peripheral naïve cell conversion (36). Although these studies did not provide a molecular mechanism to these differences, our present work indicates that they relate to specific sensitivity to factors promoting (TCR and TGF-β) and inhibiting (IL-6) Treg differentiation.…”

Section: Discussioncontrasting

confidence: 40%

Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery

Paiva

Lino

Bergman

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Most Forkhead box P3+ (Foxp3 + ) CD4 regulatory T cell (Treg) precursors are newly formed thymocytes that acquire Foxp3 expression on antigen encounter in the thymus. Differentiation of Treg, however, can also occur in the periphery. What limits this second layer of self-and nonself-reactive Treg production in physiological conditions remains to be understood. In this work, we tested the hypothesis that, similarly to thymic Treg, the precursors of peripheral Treg are immature T cells. We show that CD4 Foxp3− thymocytes and recent thymic emigrants (RTEs), contrarily to peripheral naïve mature cells, efficiently differentiate into Treg on transfer into lymphopenic mice. By varying donor and recipient mice and conducting ex vivo assays, we document that the preferential conversion of newly formed T cells does not require intrathymic preactivation, is cell-intrinsic, and correlates with low and high sensitivity to natural inhibitors and inducers of Foxp3 expression, such as IL-6, T-cell receptor triggering, and TGF-β. Finally, ex vivo analysis of human thymocytes and peripheral blood T cells revealed that human RTE and newly developed T cells share an increased potential to acquire a FOXP3 bright CD25high Treg phenotype. Our findings indicating that RTEs are the precursors of Tregs differentiated in the periphery should guide the design of Treg-based therapies.tolerance | development | lymphopoiesis | polarization

show abstract

“…Although the involvement of nT reg -intrinsic pathways has been described extensively, how nT reg development is shaped by extrinsic factors remains poorly understood (43). Additionally, although a role for IL-2 to promote thymic nT reg development has been appreciated for some time (32)(33)(34), the source of IL-2-producing cells remains undefined (6).…”

Section: Discussionmentioning

confidence: 99%

Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

Shi¹,

Kalupahana²,

Turnis³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Foxp3 + regulatory T (T reg ) cells are essential for the maintenance of self-tolerance and immune homeostasis. The majority of T reg cells is generated in the thymus as a specific subset of CD4 + T cells, known as thymus-derived or natural T reg (nT reg ) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nT reg cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nT reg cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nT reg cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nT reg generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nT reg cells.

show abstract

Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control

Cited by 93 publications

References 30 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

Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery

Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

Contact Info

Product

Resources

About

Regulatory T cell differentiation of thymocytes does not require a dedicated antigen-presenting cell but is under T cell-intrinsic developmental control

Cited by 93 publications

References 30 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

Recent thymic emigrants are the preferential precursors of regulatory T cells differentiated in the periphery

Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

Contact Info

Product

Resources

About

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