Cutaneous immune responses must be tightly controlled to prevent inflammatory and allergic diseases, i.e., atopic dermatitis, psoriasis, contact dermatitis, and pemphigus vulgaris. Foxp3+ regulatory T cells (T regs) play a critical role in skin immunoregulation. T regs can be naturally generatedinthethymus,orcanbeinduceddenovofromCD4+naveTcellsintheperipheryby antigen presenting cells, especially dendritic cells (DCs). The DC system is intricate and is comprised of distinct subsets such as, skin migratory Langerhans cells, skin migratory classical dermalDCsandCD103+dermalDCs,andtissueresidentDCs.Therelativeroleofeachofthese subsetsininducingTregshasbeenuntilnowindeterminate.Usinganovelapproachthatconsists of directing antigens to different subsets of DCs in vivo using monoclonal antibodies against surface receptors, we have found strong evidence that not all DCs have the ability to induce regulatoryTcells,butinsteadskinmigratoryDCexcelinthisfunction.Thisobservationleadstomy hypothesis that these subsets of skin migratory DC are intrinsically programmed by a set of transcriptional factors to induce this type of response. Additionally, local environmental/dietary factors are also described to play a role in the generation of T regs. For instance, the vitamin A active compound retinoic acid, working in conjunction with TGF?, is known to have a positive impact in the induction of T regs in the intestinal track. Similarly, there is ample evidence in vitro suggesting that Vitamin D acts on DCs and/or T cells for generation of a tolerogenic phenotype. The contribution of the proposed research is expected to be: 1) the identification of DCintrinsic signaling pathways that program subsets of skin migratory DC to the induction of T regs, 2) the determinationoftheroleofVitamins,actingonDCsand/orTcellsinvivo,forthegenerationofT regs,and3)theevaluationofthesuppressiveactivityofinducedTregsinamousemodelofatopic dermatitis.Wearepreparedtoundertaketheproposedresearchsincewehaveallthenecessary tools for studying DC functions in vivo, as well as, ample experience with DC subsets. With my mentors, I have planned the aims to achieve a comprehensive training in molecular biology approachesandmousegeneticengineeringduringtheK99phaseoftheaward.Thisprojectisof particularrelevancebecauseinmostskininflammatorydiseasesthenumberofTregsisaltered, qualitatively and/or quantitatively, suggesting their role in the pathophysiology of the illness. A detailedcomprehensionofthemechanismsofDCmediatedTreginductionwillhelptounderstand the events that lead to the appearance of skin disease. Also, this knowledge is likely to be beneficialtothedevelopmentnewtherapeutictargetstoincreaseTreg,whichinturnwillleadto improvedtreatmentofinflammatoryskindiseasesandtheircomplications.

Public Health Relevance

Dendriticcells(DCs)arecriticallyimportantcellsoftheimmunesystem,whichhavethe capacity to increase the numbers of regulatory T cells (T regs). T regs are specialized immune cells with the ability to stop detrimental skin inflammatory responses, such as atopicdermatitis,psoriasis,contactdermatitis,andpemphigusvulgaris.Inthisproposal, we will understand the mechanisms that govern skin DCmediated generation of high numbers of T regs, with the eventual goal of manipulating these responses in vivo for therapeuticpurposes.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Transition Award (R00)
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No Study Section (in-house review) (NSS)
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Cibotti, Ricardo
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Stanford University
Schools of Medicine
United States
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Gálvez-Cancino, Felipe; López, Ernesto; Menares, Evelyn et al. (2018) Vaccination-induced skin-resident memory CD8+ T cells mediate strong protection against cutaneous melanoma. Oncoimmunology 7:e1442163
Antonio-Herrera, Laura; Badillo-Godinez, Oscar; Medina-Contreras, Oscar et al. (2018) The Nontoxic Cholera B Subunit Is a Potent Adjuvant for Intradermal DC-Targeted Vaccination. Front Immunol 9:2212
Price, Jeremy G; Idoyaga, Juliana; Salmon, Hélène et al. (2015) CDKN1A regulates Langerhans cell survival and promotes Treg cell generation upon exposure to ionizing irradiation. Nat Immunol 16:1060-8
Flacher, Vincent; Tripp, Christoph H; Mairhofer, David G et al. (2014) Murine Langerin+ dermal dendritic cells prime CD8+ T cells while Langerhans cells induce cross-tolerance. EMBO Mol Med 6:1191-204
Godefroy, Emmanuelle; Gallois, Anne; Idoyaga, Juliana et al. (2014) Activation of toll-like receptor-2 by endogenous matrix metalloproteinase-2 modulates dendritic-cell-mediated inflammatory responses. Cell Rep 9:1856-1870