Bet v 1–specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1–specific T-cell effector function in an activation-dependent.

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Bet v 1–specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1–specific T-cell effector function in an activation-dependent manner Klaus G. Schmetterer, MD, Daniela Haiderer, MSc, Victoria M. Leb-Reichl, PhD, Alina Neunkirchner, MSc, Beatrice Jahn-Schmid, PhD, Hans J. Küng, PhD, Karina Schuch, BSc, Peter Steinberger, PhD, Barbara Bohle, PhD, Winfried F. Pickl, MD Journal of Allergy and Clinical Immunology Volume 127, Issue 1, Pages 238-245.e3 (January 2011) DOI: 10.1016/j.jaci.2010.10.023 Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Scheme of multicistronic retroviral expression constructs used in this study. Function of the respective genes is indicated. Open boxes, genes; closed boxes, interposed picornaviral 2A or IRES elements. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Transgene expression levels and gating strategy for retrovirally transduced PB T cells. A, TRAV6+TRBV20+ T cells. B, TRAV6+TRBV20+FOXP3+, FOXP3+, and control T cells. In B, GFP expression served as additional gating marker. Surface TCR expression (TRBV20) and intracellular FOXP3 expression are displayed as 2 parameter dot plots. Numbers indicate cell percentages in respective quadrants. FSC, Forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Immunophenotype of transduced T cells. PB T cells gated for CD3+CD4+GFPneg or CD3+CD4+GFPhigh subsets and analyzed for expression of indicated Treg markers. Blue line, GFPhigh subset from TRAV6/TRBV20/FOXP3–transduced T cells, specific mAb; red line, GFPhigh subset from FOXP3-transduced T cells, specific mAb; green line, GFPneg subset, specific mAb; gray line, TRAV6/TRBV20/FOXP3–transduced T cells, control mAb. FSC, Forward scatter; SSC, side scatter. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 FOXP3-transduced T cells are hyporesponsive. Proliferation of retrovirally transduced PB T cells or nTreg cells stimulated with aAPCs expressing indicated molecules (A) or anti–CD3/CD28 coated microbeads in the absence (black bars) or presence (white bars) of recombinant human IL-2 (250 U/mL; B). Means + SDs of triplicates; control, empty IRES-GFP vector; asterisks indicate significance compared with TRAV6+TRBV20+ effector T cells (- IL-2). NS, Not significant. ∗∗∗P < .001. kcpm, Kilo counts per minute. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 TRAV6/TRBV20/FOXP3–transduced T cells, unlike FOXP3-transduced T cells, suppress Bet v 1–specific effector T cells on allergen-specific activation. Proliferation of TRAV6+TRBV20+ transgenic effector T cells (Teff) cultured in the absence or presence of FOXP3+, TRAV6+TRBV20+FOXP3+ T cells, or nTreg cells at a 1:1 ratio on stimulation with Bet v 1–presenting aAPCs (A) or anti-CD3/CD28 coated microbeads (B). Data show means ± SDs from triplicates. Flow-cytometric analyses of eFluor 670 cell proliferation dye–labeled Teff in the absence (black line) or presence of FOXP3+ (red line), TRAV6+TRBV20+FOXP3+ T cells (blue line), or nTreg cells (green line) at a 1:1 ratio on stimulation with Bet v 1–presenting aAPCs (C) or anti-CD3/CD28 coated microbeads (D) in the absence (upper panel) or presence (lower panel) of exogenous IL-2 (250 U/mL). NS, Not significant. ∗∗∗P < .001. kcpm, Kilo counts per minute. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Suppression of cytokine secretion of effector T cells by engineered Treg cells. A, Cytokine levels from cell culture supernatants collected after 24 hours (TNF-α, IL-2) or 48 hours (IFN-γ, IL-13). B, Intracellular staining of indicated cytokines. Numbers indicate percentages of cytokine positive cells among GFPneg (effector) cells. One representative experiment of several is shown. ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. CFSE, Carboxyfluorescein succinimidyl ester. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Percent suppression of titrated amounts of indicated transgenic Treg cells cocultured with effector T cells (Teff) on stimulation with Bet v 1–presenting aAPCs (A) or anti–CD3/CD28 coated microbeads (B). NS, Not significant. ∗P < .05; ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2011 127, 238-245.e3DOI: (10.1016/j.jaci.2010.10.023) Copyright © 2010 American Academy of Allergy, Asthma & Immunology Terms and Conditions