Tacrolimus and TGF-β act synergistically on the generation of Langerhans cells Bartlomiej Kwiek, MD, Wen-Ming Peng, MSc, Jean-Pierre Allam, MD, Andrzej.

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Tacrolimus and TGF-β act synergistically on the generation of Langerhans cells Bartlomiej Kwiek, MD, Wen-Ming Peng, MSc, Jean-Pierre Allam, MD, Andrzej Langner, MD, Thomas Bieber, MD, PhD, Natalija Novak, MD Journal of Allergy and Clinical Immunology Volume 122, Issue 1, Pages 126-132.e1 (July 2008) DOI: 10.1016/j.jaci.2008.05.005 Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Tacrolimus enhances the effect of TGF-β1 on LC-like DC generation in vitro. The gating strategy is shown in panel A. In the absence of exogenous TGF-β1, the expression of Langerin (B) and E-cadherin (C) is low. Along with the increased concentration of TGF-β1 (1 ng/mL TGF-β1; 10 ng/mL TGF-β1), the expression of E-cadherin and Langerin is augmented. Representative dot plots with the percentage of positive CD1a+ DCs depicted in the right corner are shown. CD1a+ DCs cultured with low-dose TGF-β1 and tacrolimus expressed more Langerin (D) and E-cadherin (E) than LCs-DCs treated with a low dose of TGF-β1 alone and resemble LCs treated with a high dose of TGF-β1 (n = 7). SSC-H, Sideward scatter; FSC-H, forward scatter; 7AAD, 7-amino-actinomycin-D; Tac, tacrolimus. Journal of Allergy and Clinical Immunology 2008 122, 126-132.e1DOI: (10.1016/j.jaci.2008.05.005) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Tacrolimus amplifies the effect of TGF-β1 on the expression of costimulatory molecules of LC-like DCs. Tacrolimus synergized the effect of TGF-β1, upregulating the expression of CD40 (F) and downregulating the expression of costimulatory molecules and MHC II (B-E), but did not display any additional effect on MHC I expression (A). ∗P < .05, ∗∗P < .01 (n = 10). Tac, Tacrolimus. Journal of Allergy and Clinical Immunology 2008 122, 126-132.e1DOI: (10.1016/j.jaci.2008.05.005) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A-E, Tacrolimus synergizes the inhibitory effect of TGF-β1 on DC maturation. Tacrolimus aggravates the TGF-β1–mediated downregulation of CD80, CD83, CD86, and MHC II on mature DCs. ∗P < .05, ∗∗P < .01 (n = 6). Tac, Tacrolimus. Journal of Allergy and Clinical Immunology 2008 122, 126-132.e1DOI: (10.1016/j.jaci.2008.05.005) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Tacrolimus enhances the suppressive effect of TGF-β1 on the stimulatory capacity of DCs toward T cells. Addition of tacrolimus to 1 ng/mL TGF-β1 (low TGF-β) resulted in the reduction of the stimulatory capacity of DCs at an antigen-presenting cell/T-cell ratio of 1:100 in comparison with the condition with low TGF-β1 alone in both immature DCs (A) and mature DCs with the addition of TNF-α (250 U/mL; B). Averages of triplicates of 10 experiments are presented as means ± SEMs, and the relative stimulation index is depicted on the y-axis and calculated as follows: rSI=cpm(mixedlymphocytereaction)−cpm(Tcell)/cpm(Tcell). ∗P < .05, ∗∗P < .01, and ∗∗∗P < .005. Tac, Tacrolimus. Journal of Allergy and Clinical Immunology 2008 122, 126-132.e1DOI: (10.1016/j.jaci.2008.05.005) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Treatment of AD with tacrolimus 0.1% ointment results in increased numbers of CD1a+/Langerin-positive/Lag+ cells in the epidermis. A-F, Images of microscopic evaluation of skin biopsy specimens for the expression of CD1a, as well as the LC markers Langerin and Lag, for 1 of 5 representative patients are presented. G, Results of a total of 5 experiments are shown. The number of CD1a+ epidermal cells before tacrolimus treatment significantly exceeds the number of Langerin-positive and Lag+ cells, indicating the existence of a CD1a+ non-LC population of DCs in the epidermis of patients with AD. After 1 week of tacrolimus application, the total number of epidermal CD1a+ DCs increased simultaneously with the increased amount of Langerin-positive and Lag+ LCs. Values are presented as means ± SEMs. ∗P < .05 and ∗∗P < .01 (n = 5). Bar = 100 μm. Journal of Allergy and Clinical Immunology 2008 122, 126-132.e1DOI: (10.1016/j.jaci.2008.05.005) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Higher TGF-β receptor II expression of DCs cultured with TGF-β and tacrolimus on day 2 of culture and TGF-β2 production of HaCat cells. A, Mean ± SEM of the RFI of the extracellular expression of TGF-β receptor II of differentiating DCs on day 2 of culture is shown (n = 8 experiments). B, Amount of TGF-β1 in the supernatant of HaCat cells stimulated with increasing amounts of tacrolimus, 10−9 to 10−7 mol/L, with or without TNF-α is shown as the mean ± SEM value of 3 experiments. Tac, Tacrolimus. ∗P < .05. Journal of Allergy and Clinical Immunology 2008 122, 126-132.e1DOI: (10.1016/j.jaci.2008.05.005) Copyright © 2008 American Academy of Allergy, Asthma & Immunology Terms and Conditions