Human Regulatory T Cell Analysis · T regulatory (Treg) cells are an immunoregulatory cell type that the body uses to control autoimmunity in the periphery through “dominant tolerance”

Human Regulatory T Cell AnalysisA new approach using CD127, CD25, and CD4

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Human Regulatory T Cell Analysis

A new approach using CD127, CD25, and CD4 antibodies for identification, isolation, and characterization of viable human regulatory T lymphocytes

Introduction

The hallmark feature of autoimmune disorders involves a breakdown in the immune system’s ability to recognize “self” versus “non-self”. Although most auto-reactive T lymphocytes are regulated and eliminated during thymic development, healthy individuals continue to carry self-reactive cells that escape the “recessive tolerance”. T regulatory (Treg) cells are an immunoregulatory cell type that the body uses to control autoimmunity in the periphery through “dominant tolerance”. There are several types of Treg cells that include natural CD4+ Treg cells, Th3 cells, Tr1 cells, and CD8+ Treg cells. Natural Treg cells are developed primarily in the thymus from positively selected thymocytes with a relatively high avidity for self-antigens. Natural Treg cells represents approximately 5 – 10% of the total CD4+ T cell population, and can first be seen at the single-positive stage of T lymphocyte development.1 The signal to develop into Treg cells is thought to come from interactions between the T cell receptor and the complex of MHC II with self peptide expressed on the thymic stroma.2

In humans, natural Treg cells express CD4 and CD25 (CD4+CD25int-hi), and are also positive for the transcription factor forkhead box P3 (FoxP3). Experiments have shown that knocking out either the IL-2 receptor (CD25 or CD122) or its ligand IL-2, results in a lowered number of CD4+CD25+ cells, indicating a function of CD25 in Treg cell development. FoxP3 is a transcriptional repression factor of the forkhead/winged helix family and is expressed in all Treg cells that have regulatory activity. Mutations in FoxP3 are associated with the inherited autoimmune diseases scurfy and IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, and X-linked syndrome) in mouse and human, respectively.3

Other types of Treg cells that can develop in the periphery are the Tr1 and Th3 types of regulatory cells.4 Tr1 cells are CD4+CD25-FoxP3- cells that are functionally induced by interleukin-10 (IL-10). These Treg cells in turn secrete IL-10 and regulate the immune system. Th3 progenitor cells are similar to the Tr1 cells in that they are also CD4+CD25-

FoxP3-. In vitro CD4+CD25-FoxP3- cells stimulated with TGFb become CD4+CD25+FoxP3+ cells, and they have been shown to secrete TGFb.5,6

CD8+ Treg cells are less well characterized and are reportedly capable of suppressing CD4+ cells in vitro. This conclusion is based upon inhibition of proliferation of CD4 T cells during the stimulation of CD8+ Treg cells with anti-CD3 antibodies. In this case, the regulation involves a cell-cell contact-dependant mechanism. These cells also display the commonly accepted markers for Treg cells, CD25, and FoxP3, the latter of which is induced upon anti-CD3 stimulation.7

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Thymus

Negative selection

ImmatureT cell

Positive selection

Apoptotic death

CD4+ CD25+ Treg

Intrinsic

CD4+ CD25+ Treg

Periphery

Naïve T cell Effector T cell

Activation

Stimulation with immature DC and/or in the presence of IL-10and/or TGF

Induced

CD4+ CD25+ Treg

Tr1(IL-10)

Th3(IL-10)

Figure 1. Schematic representation of the role of regulatory T cells in immune function

Cell-surface characterization of human Treg cells

The constitutive expression of CD25 is considered to be a characteristic feature of Treg cells. Regulatory activity is enriched in those CD4+ T cells expressing the highest levels of CD25 (CD4+CD25hi

cells). Activated T cells up-regulate CD25 during immune responses associated with infection, making it difficult to discriminate between Treg and activated T effector cells.

There is a lack of consensus regarding the definition of high and low levels of CD25 expression which has affected the ability to obtain viable Treg cells via flow cytometric cell sorting. Ambiguity in this area has led some researchers to select only the cells expressing the highest levels of CD25, resulting in reduction of total Treg cell recovery.

Treg cells also express intra-cytoplasmic and cell-surface CTLA-4 (CD152), which is a negative regulator of cell-mediated immunity, and TNFRSF-18, also known as GITR [Glucocorticoid-induced Tumor necrosis factor (TNF) receptor family-Related], which is a member of the TNF receptor superfamily. Increased expression of CD25, as well as GITR and CD152 on activated non-regulatory T cells, suggests that expression of these molecules does not functionally define the Treg cell and raises the possibility that not all Treg cells express these molecules. Identification of a unique functional marker of Treg cells should help resolve the issue regarding the nature of the regulatory function of these cells.8


Unless otherwise specified, all products are for Research Use Only. Not intended for use in diagnostic or therapeutic procedures. Not for resale. Prices are subject to change without notice. All applications are either tested in-house or reported in the literature. See Technical Data Sheets for details.

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CD127 expression for characterization of human Tregs

At this time, the most definitive marker for identification of Treg cells is the FoxP3 transcription factor.9,10,11 However, identification of this marker requires permeabilization of the cells, making it difficult to work with or culture them once the staining is complete. Recent research from the laboratories of Barbara Fazekas de St. Groth (Centenary Institute of Cancer Medicine and Cell Biology, Sydney, Australia) and Jeffrey Bluestone (UCSF Diabetes Center, San Francisco, CA), and confirmed in our laboratories at BD Biosciences, has demonstrated that CD127 expression is down-modulated on Treg cells.16 CD127 is part of the heterodimeric IL-7 receptor that is composed of the CD127 and the common g chain, which is shared by other cytokine receptors (IL-2R, IL-4R, IL-9R, IL-15R, and IL-21R), CD127 is expressed on thymocytes, T- and B-cell progenitors, mature T cells, monocytes, and some other lymphoid and myeloid cells. Studies have shown that the IL-7R plays an important role in the proliferation and differentiation of mature T cells, and in vitro experiments show that the expression of CD127 is down-regulated following T cell activation.12,13,14

The correlation of down-regulated CD127 on T cells with high-to-intermediate expression of CD25 on Treg cells was confirmed by intracellular staining of FoxP3 antigen to identify Treg cells (Figure 2). As shown in Figure 2, the CD4 cells can be sorted into the CD127-high CD25-intermediate-to-low (CD127hiCD25int-lo) and CD127-low CD25 high-to-intermediate populations (CD127loCD25hi-int). The entire Treg population lies within the CD127loCD25hi-int fraction. The sorted CD127loCD25hi-int cells are positive for FoxP3 (Fig.1C, middle panel) while the CD127hiCD25int-lo cell fraction is completely devoid of any FoxP3 positive cells.

Brief protocol for isolating live T regulatory cells from human PBMCs

Human peripheral blood mononuclear cells (PBMCs) were enriched for CD4 cells using the BD IMag™ Human CD4 T Lymphocyte Enrichment Set - DM (Cat. No. 557939). Purities of greater than 90% were routinely attained for the enrichment. The cells were then stained with FITC anti-human CD25, PE anti-human CD127, and PerCP or PE-Cy7 anti-human CD4 (see product listing, page 9). The enriched cells were sorted, using a BD FACSAria™ cell sorter. The gates indicated in the top left panel of Figure 2A were applied to further enrich the CD127hiCD25int-lo and CD127loCD25hi-int populations. Staining with anti-FoxP3 confirmed that the entire Treg population lies within the CD127loCD25hi-int fraction (Figure 2C, lower middle panel), while the CD127hiCD25int-lo cell fraction is completely devoid of any FoxP3 positive cells (Figure 2B, middle panel).



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Pre Sort

CD

127-

PE

CD

127-

PE

CD

127-

PE

CD

4-Pe

rCP

CD

4-Pe

rCP

Perc

enta

ge

CD

4-Pe

rCP

CD

4-Pe

rCP

Perc

enta

ge

A.

B.

C.

CD25loCD127hi

CD4-PerCP vs mIgG1-APC

CD25int/hiCD127lo

CD4-PerCP vs mIgG1-APC

CD25loCD127hi

CD4-PerCP vs FoxP3-APC

CD25int/hiCD127lo

CD4-PerCP vs FoxP3-APC

Post SortCD25loCD127hi

Post SortCD25int/hiCD127lo

CD25-FITC CD25-FITC CD25-FITC

Isotype Control-APCIsotype Control-APC

FoxP3-APC

Isotype Control-APC FoxP3-APC

FoxP3-APC

Isotype Control-APCFoxP3-APC

Figure 2. Human PBMCs were enriched for CD4+ cells and then CD4+ human PBMCs were stained with PerCP anti-CD4, FITC anti-CD25 and PE anti-CD127. The cells were sorted on the BD FACSAria™ cell sorter based on their phenotypes, into CD25hi-intCD127lo and CD25int-loCD127hi populations (Panel A). The sorted cells were stained with an isotype control (APC mouse IgG1) or APC anti-human FoxP3. The CD25int-loCD127hi population stained with FoxP3 showed no increase in mean fluorescent intensity (MFI) when compared to the isotype control (Panel B) while the FoxP3 CD25hi-intCD127lo stained population displayed an increase in MFI over the isotype control (Panel C). Histograms of the isotype control (red) overlayed with the FoxP3 (blue) staining are shown at the right of the panels.



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Summary

Research at BD Biosciences and other labs (unpublished work by Dr. Fezekas de St. Groth and Dr. Bluestone) has shown that human Treg cells can be identified by their low expression of CD127. The expression pattern closely follows that of FoxP3 and indicates that CD4 T lymphocytes with low expression of CD127 and high-intermediate expression of CD25 are Treg cells. The advantage of using this marker over intracellular expression of FoxP3 is that the cells can subsequently be used in culture and other in vitro assays. Another advantage of using the sorting strategy (shown in Figure 2) is seen

natural treg (trn) induced tregs (itreg)

trn tr1 th3

Phenotype CD4+CD25int-hi, CD127lo-dim CD4+CD25neg CD4+CD25+ from CD25neg precursors

Other associated markers CTLA4+, GITR+, FoxP3+, CD127dim CD25low-variable, CD45RBlow, FoxP3- CD25low-variable, CD45RBlow, FoxP3+

Suppression Contact dependent, Granzyme B-dependent, makes TGFb

Through cytokines, produces IL-10 Through cytokines, produces TGFb

Target Cells APC & T effector cells T effector cells Not yet Identified

CD28 Involvement Thymic development & maintenance in periphery

Not for development or function Not involved

In Vivo Role Suppression of autoreactive T cells Mucosal immunity, inflammatory response Mucosal immunity, inflammatory response

In Vitro Expansion Expandable using TCR/CD28 stimulation and IL-2

CD3, IL-10, Vitamin D CD3, TGFb

in the recovery of the Treg cells. Using high expression of CD25 to identify Treg cells, other researchers have obtained a frequency of 0.6% to 7.9% of Treg cells from normal individuals. By using low CD127 expression in addition to CD25, our gating strategy increases the recovery of CD25-/int intermediate Treg cells often missed by gating of the CD25hi expressing cells alone. It can result in a greater than 2- 4 fold increase in the recovery of the Treg cells while eliminating the contaminating CD25 intermediate T-effector cells.15

Table 1. Treg Subsets



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BD Biosciences also offers the BD IMag™ Human Regulatory T Lymphocyte Separation Set – DM (Cat. No. 558142) for the isolation of Treg cells from peripheral blood mononuclear cells (PBMC). The reagent set isolates Treg cells in two stages. First, negative selection is performed using BD IMag streptavidin particles with a cocktail of biotinylated monoclonal antibodies (mAb) that recognizes antigens expressed on erythrocytes, platelets, granulocytes, monocytes, B cells, and CD8 T cells to enrich for the CD4 T lymphocytes. The CD25+CD4+ Treg cells are then isolated from the enriched CD4 T lymphocytes by positive selection. This enrichment set has been optimized for use with the BD IMagnet™ and contains sufficient reagents to label 109 PBMC.

CD4 positive

CD8 negative

CD11a high

CD25 positive

CD38 positive and negative subsets

CD45RA negative

CD45RB low

CD45RO positive

CD54 (ICAM-1) high

CD62L low and high subsets

CD86 negative

CD95 (Fas) high

CD103 positive and negative subse

CD122 (IL-2Rb) positive

CD127 low

CD134 (OX-40) positive and negative subsets

CD152 (CTLA-4) high

CD154 (CD40L) negative

FoxP3/scurfin positive

GITR high

IL-10 positive

TGFb positive

Blue indicates data that has been confirmed at BD Biosciences by flow cytometry.

antigen human

Table 2. Reported immunophenotypes of Human Treg cells.



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CD4 RPA-T4 555346 555347 555349 555348 557871 557695 557707 557922 558116

CD4 SK3 340133‡ 347327* 347324* 341654* 340443* 557852 341095* 339187* 340670† 340671† 341653† 340672† 348789* 341105† 348799†

CD4 SK3 & SK4 347413*

CD5 UCHT2 555352 555353 555355 555354

CD5 L17F12 347303* 347307* 341089* 340583* 348790* 340696† 340697† 341099† 340658† 348800†

CD8 G42-8 551347

CD8 HIT8a 555634 555635 555636

CD8 RPA-T8 555366 555367 555369 555368 557746 557696 557708 557945 558207

CD8 SK1 347313* 340046‡ 347314* 341051* 340584* 335787* 557834 339188* 340692† 340693† 341049† 340659† 335805† 348793* 348803†

CD11a (LFA-1) G43-25B 555379 555380

CD11a (LFA-1) HI111 555383 555384 559875 551131

CD11a (LFA-1) G-25.2 347983* 340874†

CD25 M-A251 555431 555432 555434 555433 557741 557753

CD25 2A3 347643* 341009* 340939* 335789* 340694† 341010† 340938† 335807†

CD38 HIT2 555459 555460 551400 555462 555461

CD38 HB7 340927* 347687* 340439* 335790* 340926† 340676† 340677† 335808† 342371*

CD45RA HI100 555488 555489 550855 555490

CD45RA L48 347723* 337167*

CD45RB MT4 555904

CD45RO UCHL1 555492 555493 559865 555494 337168* 347967* 340438†

CD54 (ICAM-1) HA58 555511 559771 555512 558046

CD54 (ICAM-1) LB-2 347977*

CD62L (L-Selectin) Dreg 56 555543 555544 559772 555545

CD62L (L-Selectin) SK11 347443* 341012*

CD62P (P-Selectin) AK-4 555523 555524 550888 551142

CD62P (P-Selectin) AC1.2 348107*

CD86 (B70/B7-2) 2331 (FUN-1) 555657 555658 555660 555659

CD86 (B70/B7-2) IT2.2 555665 555666

CD95 (Fas/APO-1) DX2 555673 555674 558814 559773 340479* 340480* 340481*

CD103 Ber-ACT8 550259 550260 340945* 340998* 340944† 340997†

CD122 (IL-2Rb) Mik-b2 554522

CD122 (IL-2Rb) Mik-b3 554525

CD122 (IL-2Rb) TU27 340254*

CD127 hIL-7R-M21 557938

CD134 (OX-40) ACT35 555837 555838 551500

CD134 (OX-40) L106 340420*

CD137 (4-1BB) 4B4-1 555956 550890 551137

CD152 (CTLA-4) BNI3 555853 555855 555854

CD154 (CD40L) TRAP1 555699 555700 555702 555701

CD154 (CD40L) 89-76 340477*

IL-10 JES3-19F1 554706 554707 559330

IL-10 JES3-9D7 554498 559337

specificity clone fitc pe percp percp- apc pe-cy5 pe-cy7 apc-cy7 alexa alexa alexa pacific amcyan cy5.5 fluor® fluor® fluor® blue 488 647 700

Table 3. Fluorochrome-conjugated monoclonal antibodies for immunophenotyping of Human Treg cells.

All reagents are for research use only (RUO), except as indicated.

*RUO (GMP); †ASR; ‡IVD



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Human Regulatory T Lymphocyte Separation Set – DM 558142

Human CD4 T Lymphocyte Enrichment Set – DM 557939

Anti-CD25 Magnetic Particles – DM 2A3 558005

Anti-Allophycocyanin (APC) Magnetic Particles – DM 557932

BD IMagnet 552311

BD IMag Buffer (10X) 552362

description clone format cat. no.

Table 4. BD IMag™ and BD Pharmingen™ reagents for enrichment and isolation of Treg cells

Anti-Human CD3 UCHT1 NA/LE 555329

Anti-Human CD28 CD28.2 NA/LE 555725

Anti-Human CD152 (CTLA-4) BNI3 NA/LE 555850

Human IL-2 recombinant protein 554603

description clone format cat. no.

Table 5. BD Pharmingen™ reagents for costimulation or inhibition of Treg cells

References

1. Piccirillo CA, Thornton AM. Cornerstone of peripheral tolerance: naturally occurring CD4+CD25+ regulatory T cells. Trends Immunol. 2004; 25(7):374-380.

2. Fehervari Z, Sakaguchi S. Development and Function of CD25+CD4+ regulatory T cells. Curr. Opin. Immunol. 2004;16:203-208.

3. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor FoxP3. Science 2003; 299(5609):1057-1061

4. Bluestone JA, Tang Q. How do CD4+CD25+ regulatory T cells control autoimmunity? Curr. Opin. Immunol. 2005;17:638-642.

5. Roncarolo MG, Bacchetta R, Bordignon C, Narula S, Levings MK. Type 1 T regulatory cells. Immun. Rev. 2001;182:68-79.

6. Huber S, Schramm C, Lehr HA, Mann A, Schmitt S, Becker C, Protschka M, Galle PR, Neurath MF, Blessing M. Cutting Edge: TGFb signaling is required for the in vivo expansion and immunosuppressive capacity of regulatory CD4+CD25+ T cells. J. Immunol. 2004: 173(11):6526-31.

7. Bisikirska B, Colgan J, Luban J, Bluestone JA, Herold KC. TCR stimulation with modified anti-CD3 mAb expands CD8+ T cell population and induces CD8+CD25+ Tregs. J. Clin. Invest. 2005;115:2904-2913.

8. Dejaco C, Duftner C, Grubeck-Loebstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune disease. Immunology 2006;117:289-300.

9. Fontenot JD, Rudensky AY. A well adapted regulatory contrivance: regulatory T cell development and the forkhead family transcription factor Foxp3. Nat. Immunol. 2005; 6(4):331-337.

10. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological self tolerance to self and non-self. Nat. Immunol. 2005;6(4):345-352.

11. Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY. Regulatory T cell lineage specification by the forkhead transcription factor Foxp3. Immunity. 2005;22:329-341.

12. Hofmeister R, Khaled AR, Benbernou N et al. Interleukin-7: Physiological roles and mechanism of action. Cytokine Growth Factor Rev. 1999;10:41.

13. Appasamy PM. Biological and clinical implications of interleukin-7 and lymphopoiesis. Cytokines Cell Mol Ther. 1999; 5:25.

14. Fitzgerald KA, O’Neill LAJ, Gearing AJH et al. eds. The Cytokine Facts Book, San Diego: Academic press, Inc., 2001

15. Unpublished data by BD Biosciences.

16. Liu W, Putnam AL, Xu-yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper D, Ziegler S, and Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Tregs J. Exp. Med. 2006; manuscript submitted.



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Documents

Human Regulatory T Cell Analysis · T regulatory (Treg) cells are an immunoregulatory cell type that the body uses to control autoimmunity in the periphery through “dominant tolerance”