The epidermis of the skin is a barrier surface that serves as the front line of defense against a diverse array of potential pathogens. In addition to providing a physical barrier, the epidermis is home to several categories of long-lived immune cell types most notably Langerhans cells (LC) and CD8+ resident memory T cells (Trm). LC transport antigen acquired in the epidermis to the lymph node where they promote the development of effective T cell responses against fungi and likely other extracellular pathogens. Trm cells are a recently appreciated subset of memory T cell that are required for efficient protection against secondary Vaccinia virus and Herpes Simplex virus infections. LC and Trm are also responsible for many autoimmune diseases such as graft vs. host disease, vitiligo, and alopecia areata. Despite the importance of these cells, the mechanism(s) and factors governing their retention in the epidermal niche have been poorly described. TGF? is released from cells as a latent form (LAP-TGF?) and is activated by the integrins ?v?6 and ?v?8 on keratinocytes (KC). The regulated expression of ?v?6 and ?v?8 by KC directly controls epidermal residence of both Trm and LC during steady-state and after UV irradiation. This observation that the availability of the epidermal niche for leukocyte residence is determined by KC activation of TGF? raises the possibility that pharmacologic reduction of active TGF? could be used to alter leukocyte epidermal residence to therapeutic benefit. The goal of this competitive renewal is understand the basic biology of leukocyte retention within the epidermal niche in order to rationally translate these findings into approaches that deplete epidermal leukocytes in disease states. We propose to test the hypothesis that reduced expression of integrins by regionally segregated subsets of KC occurs in response to all inflammatory stimuli and results in loss of epidermal LC and Trm. We will also test the hypothesis that in response to inflammatory stimuli other KC subsets maintain integrin expression thereby leaving intact a local niche LC and Trm. This would allow for LC migration and open some of the epidermal niche for Trm specific for the new pathogen while also retaining LC that can repopulate the epidermis and Trm specific to previously encountered pathogens. Finally, we will test the hypothesis that therapies inhibiting active TGF? reduce LC and Trm in patients and can ameliorate disease in an animal model of vitiligo.

Public Health Relevance

We have observed that the availability of the epidermal niche for leukocyte residence is determined by KC activation of TGF?. This raises the possibility that pharmacologic reduction of active TGF? could be used to alter leukocyte epidermal residence to therapeutic benefit. The goal of this competitive renewal is to understand the basic biology of leukocyte retention within the epidermal niche in order to rationally translate these findings into approaches that deplete epidermal leukocytes in disease states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR060744-07
Application #
9191681
Study Section
Special Emphasis Panel (ZRG1-MOSS-U (02)S)
Program Officer
Cibotti, Ricardo
Project Start
2011-09-15
Project End
2021-05-31
Budget Start
2016-08-05
Budget End
2017-05-31
Support Year
7
Fiscal Year
2016
Total Cost
$465,050
Indirect Cost
$157,799
Name
University of Pittsburgh
Department
Dermatology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Strandt, Helen; Pinheiro, Douglas Florindo; Kaplan, Daniel H et al. (2017) Neoantigen Expression in Steady-State Langerhans Cells Induces CTL Tolerance. J Immunol 199:1626-1634
Mohammed, Javed; Beura, Lalit K; Bobr, Aleh et al. (2016) Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-?. Nat Immunol 17:414-21
Huang, Huizhen; Kuzirian, Marissa S; Cai, Xiaoyun et al. (2016) Generation of a NK1R-CreER knockin mouse strain to study cells involved in Neurokinin 1 Receptor signaling. Genesis 54:593-601
Kashem, Sakeen W; Kaplan, Daniel H (2016) Skin Immunity to Candida albicans. Trends Immunol 37:440-50
Scholz, Felix; Naik, Shruti; Sutterwala, Fayyaz S et al. (2015) Langerhans Cells Suppress CD49a+ NK Cell-Mediated Skin Inflammation. J Immunol 195:2335-42
Kashem, Sakeen W; Igyarto, Botond Z; Gerami-Nejad, Maryam et al. (2015) Candida albicans morphology and dendritic cell subsets determine T helper cell differentiation. Immunity 42:356-366
Kashem, Sakeen W; Riedl, Maureen S; Yao, Chen et al. (2015) Nociceptive Sensory Fibers Drive Interleukin-23 Production from CD301b+ Dermal Dendritic Cells and Drive Protective Cutaneous Immunity. Immunity 43:515-26
Hordinsky, Maria; Kaplan, Daniel H (2014) Low-dose interleukin 2 to reverse alopecia areata. JAMA Dermatol 150:696-7
Igyarto, Botond Z; Kaplan, Daniel H (2013) Antigen presentation by Langerhans cells. Curr Opin Immunol 25:115-9
Welty, Nathan E; Staley, Christopher; Ghilardi, Nico et al. (2013) Intestinal lamina propria dendritic cells maintain T cell homeostasis but do not affect commensalism. J Exp Med 210:2011-24

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