Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3–positive regulatory versus TH2 effector cells to.

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Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3–positive regulatory versus TH2 effector cells to cause allergy John A. Altin, BSc, Lei Tian, MSc, Adrian Liston, PhD, Edward M. Bertram, PhD, Christopher C. Goodnow, PhD, Matthew C. Cook, MB, BS, PhD Journal of Allergy and Clinical Immunology Volume 127, Issue 5, Pages 1277-1285.e5 (May 2011) DOI: 10.1016/j.jaci.2010.12.1081 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A, Histograms and plotted median fluorescence intensity (MFI) of CD25 expression on CD4+ T cells from Card11unm or wild-type mice after overnight CD3 plus CD28 stimulation. Replicates are from 3 separate stimulated wells. B, Treg cell abundance in lymph nodes from wild-type or Card11unm mice determined by means of intracellular staining for Foxp3 gated on CD4+ T cells. C, Expression of CD44, IFN-γ, IL-4, and IL-17 by lymph node CD4+ T cells from Card11unm and wild-type mice after 4 hours' ex vivo phorbol 12-myristate 13-acetate plus ionomycin stimulation and intracellular staining. D, IL-4–producing CD4+ T-cell frequency in blood from Card11unm mice of a range of ages and their wild-type or heterozygous littermates detected by means of intracellular staining as above. n.s., Not significant. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, Macroscopic appearance and histology of an affected Card11unm mouse showing pruritic skin lesion and mast cell infiltrates (arrows) revealed by Alcian blue staining. B, Plasma IgE concentrations in αβ T cell–sufficient or αβ T cell–deficient mice carrying either wild-type or mutant alleles of Card11, as quantified by means of ELISA. C, Incidence of dermatitis in αβ T cell–sufficient or αβ T cell–deficient Card11unm mice. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A and B, Percentage of IL-4–producing cells among lymph node CD44hiCD4+ T cells (Fig 3, A) or incidence of dermatitis (Fig 3, B) in Card11unm mice that were either untreated or injected intravenously with 106 sorted CD4+ T cells from a wild-type Ly5a donor 10 weeks prior, as measured previously. C, Representative plots (upper) and quantitation (lower) showing the representation of donor-derived (Ly5a+, shown in blue) and recipient-derived (Ly5b+, shown in red) cells among lymph node CD44lo, CD44hi, TH1, TH2, TH17, or Treg cell subsets in the recipient mice described in Fig 3, A. D, Representation of donor-derived (Ly5a+) cells (left) or total IL-4–producing cells (right) among the CD44hiCD4+ T-cell compartment in the peripheral blood of Card11unm mice that were either untreated or injected intravenously with 105 sorted Treg (CD4+CD25+) or Teff (CD4+CD25−CD44hiCD62Llo) cells 10 weeks prior. Data are representative of 2 independent experiments. n.s., Not significant. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 A, Incidence of dermatitis in Card11unmFoxp3null mice compared with single-mutant and wild-type control animals. B-D, Quantitation of CD4+ T-cell expression of CD44, IFN-γ, and IL-4 or the ratio of IL-4+ cells/IFN-γ+ cells from mice of the 4 genotypes measured by means of ex vivo stimulation and intracellular cytokine staining, as previously described. Data are collated from 4 independent experiments. n.s., Not significant. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

A, Plotted median fluorescence intensity (MFI) of CD25, Foxp3, IRF4, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), and glucocorticoid-induced TNF-related receptor (GITR) on lymph node Foxp3+CD4+ T cells from Card11unm or wild-type mice measured by means intracellular staining. B, Frequency of Foxp3+ cells among CD4+CD8− thymocytes from Card11unm or wild-type mice. n.s., Not significant. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Expression of GATA3 on the CD40loIL-4−, CD44hiIL-4−, or CD44hiIL-4+CD4+ T-cell subsets (as indicated) from a Card11unm mouse, as detected by means of ex vivo restimulation followed by intracellular cytokine staining. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

IL-4 production by CD4+ T cells from nontransgenic or OT-II TCR transgenic Card11unm or control mice detected by means of ex vivo restimulation followed by intracellular cytokine staining. Cells expressing the transgenic TCR are Vβ5+. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Reconstitution of the Foxp3+ population in Card11unm mice after wild-type CD4+ T-cell transfer. Percentage of Foxp3+ cells among lymph node CD4+ T cells from mice that were either untreated or injected intravenously with 106 sorted CD4+ T cells from a Ly5a donor 10 weeks prior. Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

A and B, Dilution of carboxyfluorescein succinimidyl ester (CFSE) and production of IFN-γ and IL-4 by wild-type or Card11unm cells after culture of sorted naive CD4+ splenocytes under TH0-, TH1-, or TH2-polarizing conditions for 5 days. C, Dilution of CFSE and production of IL-17 by wild-type or Card11unm cells after culture of sorted naive CD4+ splenocytes under TH0- or TH17-polarizing conditions for 3 days. D, Quantitation of the percentage of cytokine-producing cells at the end point of the TH1, TH2, or TH17 cultures (3 mice per genotype). Journal of Allergy and Clinical Immunology 2011 127, 1277-1285.e5DOI: (10.1016/j.jaci.2010.12.1081) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions