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Comparative Study
. 2010 Mar 30;107(13):5919-24.
doi: 10.1073/pnas.1002006107. Epub 2010 Mar 15.

VSports手机版 - Genomic definition of multiple ex vivo regulatory T cell subphenotypes

Markus Feuerer  1 , Jonathan A Hill, Karsten Kretschmer, Harald von Boehmer, Diane Mathis, Christophe Benoist
Affiliations
Comparative Study

Genomic definition of multiple ex vivo regulatory T cell subphenotypes

Markus Feuerer et al. Proc Natl Acad Sci U S A. .

Abstract

Regulatory T (Treg) cells that express the Foxp3 transcription factor are essential for lymphoid homeostasis and immune tolerance to self. Other nonimmunological functions of Treg cells, such as controlling metabolic function in adipose tissue, are also emerging. Treg cells originate primarily in the thymus, but can also be elicited from conventional T cells by in vivo exposure to low-dose antigen or homeostatic expansion or by activation in the presence of TGFbeta in vitro VSports手机版. Treg cells are characterized by a distinct transcriptional signature controlled in part, but not solely, by Foxp3. For a better perspective on transcriptional control in Treg cells, we compared gene expression profiles of a broad panel of Treg cells from various origins or anatomical locations. Treg cells generated by different means form different subphenotypes and were identifiable by particular combinations of transcripts, none of which fully encompassed the entire Treg signature. Molecules involved in Treg cell effector function, chemokine receptors, and the transcription factors that control them were differentially represented in these subphenotypes. Treg cells from the gut proved dissimilar to cells elicited by exposure to TGFbeta in vitro, but instead they resembled a CD103(+)Klrg1(+) subphenotype preferentially generated in response to lymphopenia. .

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Conflict of interest statement (VSports)

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Distinct genomic profiles in Foxp3+ cells are elicited by different means. (A) “SignatureMatch” analysis showing the normalized expression of Treg signature probes (30) across different Treg cell populations. Raw expression values were normalized to 1 or 0 for spleen Treg and spleen Tconv, respectively, and displayed as a heat map where red represents the expression value of a gene at the same or a greater level than what was found for spleen Treg, whereas black represents the expression value of a gene that is at the same or a lower level than that of spleen Tconv (Upper). (Right) The underexpressed Treg signature, green representing the expression value of a gene at the same or a greater level than what was found in spleen Tconv and black representing the expression value of a gene that is at the same or a lower level than that of spleen Treg. Highlighted gene regions are discussed in the text (and in Fig. S1). Additional description of cell types can be found in Table S1. (B) “2D reference plots” with Treg overexpressed and Treg underrepresented genes on the x and the y axis, respectively. The relative coordinates for each population are calculated for these two traits and plotted on the 2D panel (47). (C) Principal component analysis. Three components are displayed and the different T cell groups are plotted relative to the component distribution. (D) Most influential genes that discriminate between the first three principal components are shown as a heat map.
Fig. 2.
Fig. 2.
Effector, homing, and transcription factor molecules in Treg phenotypes. Comparison is shown of normalized expression values of candidate effector molecules (A), chemokine receptors (B), and transcription factors (C). Data are row normalized and presented as a heat map where red and black represent the highest- and lowest-expressed genes, respectively. *, inactive probe due to genetic knock-in.
Fig. 3.
Fig. 3.
Normal equivalents of homeostatically converted Treg cells. (A) (Left) RNA expression of Klrg1 and CD103 in different Treg and Tconv populations determined by microarray (values are shown in arbitrary units). Protein expression of Klrg1 and CD103 in homeostatically converted and nonconverted CD4 T cells was determined by FACS (Right). (B) Expression pattern of Foxp3, Klrg1, and CD103 in CD4 T cells isolated from different organs from C57BL/6 mice. Representative dot plots are shown (Left) and summarized as means ± SD (Right). (C) Gene expression prolife of CD103−KLRG1−, CD103+KLRG1−, and CD103+KLRG1+ Foxp3+Treg cells isolated from peripheral LN. Data are represented as “Signature Match” analysis of the Treg overexpressed signature (30). (D) Comparison of the fraction of KLRG1-expressing cells among Foxp3+ Treg cells in 7-day-old perinatal and 6-week-old adult mice. Means ± SD of three mice per group are shown. * indicates significant difference by t test (P < 0.05). (E) Comparison of BrdU incorporation of KLRG1-positive and -negative Treg cells. Representative dot plots with the means ± SD of the gated population are shown for three independent experiments.
Fig. 4.
Fig. 4.
In vivo equivalents of TGFβ-converted Tregs? (A) TGFβ signature probes were plotted on several groups for comparison, from left to right, of in vitro TGFβ converted T cells vs. activated T cells and lymph node (LN)-, spleen (Sp)-, or lamina propria (LP)-derived Treg cells compared to thymus Tregs. (B) Fold-change–fold-change plots showing the influence of the lamina propria environment on gene expression in Treg and Tconv cells. The y axis compares the expression profiles between LP and Sp Treg cells, whereas the x axis compares the expression profiles of LP and Sp Tconv cells. Highlighted in red are the TGFβ signature genes. (C) SignatureMatch profile of the Treg Up signature plotted using Sp Treg cells as the full signature and Sp Tconv cells as the baseline. Groups shown are TGFβ-converted T cells compared to LP or CD103+Klrg1+ Treg cells. (D) The Foxp3+CD103+Klrg1+ phenotype is found at the highest frequency in the LP. Cells were gated on being positive for both CD4 and Foxp3. (E) OT-II conversion mediated by oral ovalbumin is enhanced by the presence of TGFβ. Congenically marked (CD45.2+) naive OT-II CD4+ T cells (CD25−CD44lo) were identified in the mesenteric lymph nodes of CD45.1+ recipient mice 7 days after i.v. transfer. Recipient mice received either normal drinking water (no Ova) or water supplemented with 1.5% ovalbumin (PBS and anti-TGF). Mice were also injected with either anti-TGF antibody (1D11, 1 mg/mouse × 3 over 7 days) or PBS. FACS plots show the expression of Foxp3 and CD103 on OT-II donor cells. Graphs to the right summarize the data for individual mice from three independent experiments. P values were determined by t test.
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