The Late Endosomal Adaptor Molecule p14 (LAMTOR2) Regulates TGFβ1-Mediated Homeostasis of Langerhans Cells Florian Sparber, Christoph H. Tripp, Kerstin.

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The Late Endosomal Adaptor Molecule p14 (LAMTOR2) Regulates TGFβ1-Mediated Homeostasis of Langerhans Cells Florian Sparber, Christoph H. Tripp, Kerstin Komenda, Julia M. Scheffler, Björn E. Clausen, Lukas A. Huber, Nikolaus Romani, Patrizia Stoitzner Journal of Investigative Dermatology Volume 135, Issue 1, Pages 119-129 (January 2015) DOI: 10.1038/jid.2014.324 Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Langerin-specific deletion of p14 leads to loss of Langerin+ migratory dendritic cells (DCs) in the skin-draining lymph nodes (LNs) of adult mice. (a) FACS analysis of skin-draining LNs of adult control and Langerin-p14del mice for various DC subsets. LN-resident (CD11chighMHC-class IIint DCs) and migratory DCs (CD11cintMHC-class IIhigh) were analyzed by pregating on viable cells and analysis of the chemokine receptor CCR7. Plasmacytoid DCs were characterized as MHC-class IIlowPDCA1+ DCs among CD11c+ pregated viable cells. One representative experiment is shown in a. Combined data for percentages of LN-resident DCs, pDCs, and migratory DCs from four individually analyzed mice per genotype are analyzed in b, c, and d. Mean±SD is shown, ***P<0.001. MHC, major histocompatibility complex. Journal of Investigative Dermatology 2015 135, 119-129DOI: (10.1038/jid.2014.324) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 LC numbers decline 3 weeks after birth in Langerin-p14del mice. (a, b) FACS analysis of newborn and adult whole skin obtained from Langerin-p14del and control mice for the presence of CD11c+Langerin+CD103− LCs at defined time points after birth. (c) Expression of CD86 and Langerin by Langerin+CD103− LCs is shown as mean fluorescence intensity (MFI). (a, d) FACS analysis of newborn and adult skin obtained from Langerin-p14del and control mice for the presence of dermal CD11c+Langerin+CD103+ DCs at defined time points. One representative experiment is shown in a; combined data from six mice per genotype and time point in b, c, and d. Mean±SD is shown, *P<0.05. (e) Epidermis from adult control and Langerin-p14del mice was stained for major histocompatibility complex (MHC)-class II; scale bar=100 μm (f) FACS analysis of epidermal cell suspension, derived from 21-day-old Langerin-p14del (second density plot) and control mice (first density plot), for the maturational phenotype of LCs. LCs were identified by the expression of CD11c and Langerin. One representative experiment out of two is shown in f. Journal of Investigative Dermatology 2015 135, 119-129DOI: (10.1038/jid.2014.324) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 Loss of Langerhans cells (LCs) reduces contact hypersensitivity (CHS) response to trinitrochlorobenzene (TNCB). (a) Scheme for experimental setup. (b) Measurement of the ear thickness and the calculation of the actual ear swelling of Langerin-p14del and control mice, treated either with low-dose (0.25%, left side) or high-dose (0.5%, right side) TNCB. Summary of three experiments is shown; mean±SD is shown; *P<0.05, **P<0.01, and ***P<0.001. Journal of Investigative Dermatology 2015 135, 119-129DOI: (10.1038/jid.2014.324) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 CD11c-specific deletion of p14 impairs responsiveness of bone marrow–derived dendritic cells (BMDCs) toward transforming growth factor β1 (TGFβ1). (a, b) FACS analysis of Langerin+ Langerhans cell (LC)-like BMDCs (LCL-BMDCs) cultured in the presence of GM-CSF±TGFβ1 for 8 days. Viable CD11c+ BMDCs were analyzed for Langerin expression. Maturation was determined by CD86 expression on LCL-BMDCs. One representative experiment for TGFβ-supplemented cultures in a; combined data from at least three individually analyzed mice per genotype in b. Mean±SD is shown. (c, d) FACS analysis of total CD11c+ BMDCs cultured in the presence of GM-CSF±TGFβ1 for 8 days. Maturation was determined by the expression of major histocompatibility complex (MHC)-class II, CD86, and CD40 on CD11c+ BMDCs. BMDC culture scheme in c, scale bar=50 μm; combined data from three individually analyzed mice per genotype in d. Mean±SD is shown, *P<0.05, **P<0.01. Journal of Investigative Dermatology 2015 135, 119-129DOI: (10.1038/jid.2014.324) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 5 Ablation of p14 reduces the expression of transforming growth factor βRII (TGFβRII) and the surface binding of TGFβ1 to bone marrow–derived dendritic cells (BMDCs). (a) Analysis of CD11c+ BMDCs, obtained from CD11c-p14del and control mice, on day 8 of culture for the expression of the TGFβRII. BMDCs were analyzed by discriminating between CD11c+CD86− and CD11c+CD86+ BMDCs. (b, c) Binding of biotinylated TGFβ1 to day 8 CD11c+ BMDCs cultured without (upper row) or with TGFβ1 (lower row); isotype, gray filled; control mice, dotted line; CD11c-p14del mice, black line. Biotinylated soy protein or preincubation with an anti-TGFβ1 blocking antibody was used for negative controls. One representative experiment of each BMDC culture condition in a and b, combined data from four individually analyzed mice per genotype and culture condition in c. Mean±SD is shown. (d) Microscopic analysis of (green fluorescent) TGFβ1 surface binding on day 8 CD11c-p14del and control BMDCs. Preincubation with an anti-TGFβ1 blocking antibody was used as negative control. Scale bar=10 μm. *P<0.05. Journal of Investigative Dermatology 2015 135, 119-129DOI: (10.1038/jid.2014.324) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 6 TGFβRII is downregulated on Langerhans cells (LCs) upon p14 deletion. (a, b) FACS analysis of LCs isolated from the epidermis of 21-day-old Langerin-p14del and control mice for the expression of TGFβRII. Histogram shows the expression of CD86 and TGFβRII on major histocompatibility complex (MHC)-class II+ LCs. One representative experiment in a; combined data from three individually analyzed mice per genotype in b. Mean±SD is shown, *P<0.05. Journal of Investigative Dermatology 2015 135, 119-129DOI: (10.1038/jid.2014.324) Copyright © 2015 The Society for Investigative Dermatology, Inc Terms and Conditions