# Regulated Activation of Latent-TGFb Determines Leukocyte Occupancy of the Epidermal Niche

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2020 · $508,664

## Abstract

Abstract
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.
TGFβ is released from cells as a latent form (LAP-TGFβ) and is activated by the integrins αvβ6 and αvβ8 on
keratinocytes (KC). The regulated expression of αvβ6 and αvβ8 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 TGFβ raises the possibility that
pharmacologic reduction of active TGFβ 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 TGFβ reduce LC and Trm in patients and can ameliorate disease
in an animal model of vitiligo.

## Key facts

- **NIH application ID:** 9938431
- **Project number:** 5R01AR060744-11
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Daniel H Kaplan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $508,664
- **Award type:** 5
- **Project period:** 2011-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938431

## Citation

> US National Institutes of Health, RePORTER application 9938431, Regulated Activation of Latent-TGFb Determines Leukocyte Occupancy of the Epidermal Niche (5R01AR060744-11). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9938431. Licensed CC0.

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