Cutting Edge: Human CD4−CD8− Thymocytes Express FOXP3 in the Absence of a TCR

Tuovinen, Heli; Kekäläinen, Eliisa; Rossi, L; Puntila, Juha; Arstila, T. Petteri

doi:10.4049/jimmunol.180.6.3651

Cited by 26 publications

(19 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Section: Introductionmentioning

confidence: 99%

“…Suppressive function was ascribed to CD25 1 CD4SP thymocytes, but also to the CD25 1 DP and CD25 1 CD8SP populations [11,12,14,[16][17][18]. We and others have assessed FOXP3 expression in the human thymus and reported its expression at early stages of T-cell development, likely impacting on the diversity and autoreactivity of the Tregcell repertoire [19][20][21].We investigated here the development of Treg cells in the human thymus and provide evidence that a considerable fraction of FOXP3 1 SP cells derives from FOXP3 1 DP thymocytes. Our data support a model whereby FOXP3 expression in human DP thymocytes is associated with the expression of a functional IL-7 receptor, as well as of markers of Treg-cell activation, which decline as thymocytes mature.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Differentiation of human thymic regulatory T cells at the double positive stage

et al. 2011

View full text Add to dashboard Cite

Treg cells, best identified by the expression of the transcription factor FOXP3, play a crucial role in maintaining self-tolerance. Natural Treg cells constitute an independent thymusderived T-cell lineage whose developmental program in humans is still ill-defined. Here, we provide evidence of a Treg-cell differentiation pathway at the double positive (DP) stage, prior to commitment to the CD4 1 or CD8 1 lineage, in pediatric thymuses. FOXP3 1 DP cells displayed a functional IL-7 receptor and increased Bcl-2 levels that may protect them from cell death/negative selection, and an activated/suppressive phenotype that was lost as CD4 single positive (SP) cells matured and acquired egress markers. A subpopulation of FOXP3 1 DP thymocytes expressing CD103 likely represents the precursor of FOXP3 1 CD8SP cells, which homogeneously expressed this mucosal-homing molecule. Finally, co-cultures of DP thymocytes with primary thymic epithelial cells and multiple linear regression analyses support that FOXP3 1 SP cells are largely derived from FOXP3 1 DP thymocytes. Overall, our data suggest that human Treg-cell lineage commitment significantly occurs at the DP stage with possible implications for the diversity and autoreactivity of the natural Treg-cell repertoire.Key words: FOXP3 . Human T-cell development . Treg cells . Thymus Supporting Information available online IntroductionThe thymus is essential for the establishment and renewal of the peripheral T-cell compartment with a diverse repertoire, able to efficiently respond to novel pathogens, yet tolerant to selfantigens. Tolerance is at least partly achieved through the thymic production of a subset of T cells termed ''natural'' Treg cells. Treg cells modulate the activation and function of other T cells, as well as of other cell populations of the immune system, playing important roles not only in the prevention of autoimmune diseases, but also in other clinical settings, such as tumor immunity and persistent infections [1,2]. Currently, the forkhead/winged-helix transcription factor FOXP3 is considered as the best available marker to identify Treg cells. The essential role of FOXP3 in human Treg-cell development and function is attested by the association of FOXP3 defects with the fatal condition IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome [3]. Although understanding Treg-cell development in the human thymus is critical for their manipulation [4], the developmental program that Treg-cell precursors undergo to give rise to mature FOXP3 1 cells is still unclear. 3604T-cell development proceeds through a series of stages that can be tracked by the expression of CD3, CD4 and CD8. In humans, CD4 -CD8 -CD3 -triple negative cells first acquire CD4 (CD4 1 immature single positive) and then CD8 to become CD4 1 CD8 1 (double positive, DP) cells. DP cells bearing TCR-ab complexes able to engage self-MHC molecules are signaled to survive (positive selection) and to differentiate into functionally mature CD4 1 single positive (CD4SP; CD4 1 CD8...

show abstract

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Differentiation of human thymic regulatory T cells at the double positive stage

et al. 2011

View full text Add to dashboard Cite

show abstract

“…In fact, a careful examination of the immunohistochemical analysis of published data (23) indicated that in both mouse thymus and spleen, expression of neither FoxP3 nor the knocked in diphtheria toxin receptor is restricted to mature T cells. Meanwhile, expression of FoxP3 in TCR-negative cells was reported in human thymus (27).…”

Section: Homeostatic Proliferation In the Mice With Germlinementioning

confidence: 99%

Homeostatic Proliferation in the Mice with Germline FoxP3 Mutation and its Contribution to Fatal Autoimmunity

Chang¹,

Zheng²,

Liu

2008

The Journal of Immunology

View full text Add to dashboard Cite

FoxP3 has emerged as a critical regulator for the development and function of regulatory T cells. Recent studies by several groups have demonstrated that FoxP3 is expressed outside T cell lineages. In this context, we have reported that germline mutation of FoxP3 caused defective thymopoiesis, although its potential contribution to autoimmune diseases has not been analyzed. In this study, we report that, during perinatal period, germline mutation of FoxP3 in scurfy mice caused lymphopenia in the spleen and massive homeostatic proliferation, characterized by the independence from cognate Ags and expression of bona fide markers for homeostatic proliferation. The homeostatic proliferation is suppressed by increases in T cell numbers but not by adoptive transfer of regulatory T cells (Treg). Adoptive transfer of Treg-containing bulk T cells was dramatically more effective than transfer of either Treg alone or Treg-depleted CD4 T cells in curing the scurfy mice. Our data demonstrated that FoxP3 mutation not only ablates Treg, but also dramatically increased homeostatic proliferation during the perinatal period. Homeostatic proliferation acts in concert with Treg defects in causing acute and fatal autoimmune diseases in the FoxP3 mutant mice. These results demonstrated that germline mutation of FoxP3 caused two defects that work in concert to cause lethal autoimmunity.

show abstract

“…The expression of T cell receptor-associated proteins during T cell ontogeny in man. (2). However, contrary to their claim, CD3 is not a fully reliable surrogate for ␣␤ TCR on thymocytes, and surface CD3 is not always associated with a TCR.…”

mentioning

confidence: 53%

“…Perhaps Battaglia et al refer to the known propensity of WT31 to cross-react with an epitope formed by ␥␦ TCR and CD3 (4), but we fail to see how in the present context this could be a source of error. Arguing against the functional expression of an ␣␤ TCR is also the fact that the FOXP3 ϩ DN thymocytes did not express CD5 or CD69, molecules up-regulated in response to TCR signaling (2).…”

mentioning

confidence: 99%