Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing

Jung U Shin,Jung U Shin,Jung U Shin,Lauren Herron,Hasan E Abaci,Yanne Doucet,Angela M Christiano,Angela M Christiano,Alberto Pappalardo,Brigitte Sallee,Zongyou Guo,Joanna Jackow,Eddy Hsi Chun Wang

doi:10.1038/s41598-020-60275-0

Abstract

Drug screening studies for inflammatory skin diseases are currently performed using model systems that only partially recapitulate human diseased skin. Here, we developed a new strategy to incorporate T cells into human 3D skin constructs (HSCs), which enabled us to closely monitor and quantitate T cell responses. We found that the epidermis promotes the activation and infiltration of T cells into the skin, and provides a directional cue for their selective migration towards the epidermis. We established a psoriatic HSC (pHSC) by incorporating polarized Th1/Th17 cells or CCR6+CLA+ T cells derived from psoriasis patients into the constructs. These pHSCs showed a psoriatic epidermal phenotype and characteristic cytokine profiles, and responded to various classes of psoriasis drugs, highlighting the potential utility of our model as a drug screening platform. Taken together, we developed an advanced immunocompetent 3D skin model to investigate epidermal-T cell interactions and to understand the pathophysiology of inflammatory skin diseases in a human-relevant and patient-specific context.

Highlights

Drug screening studies for inflammatory skin diseases are currently performed using model systems that only partially recapitulate human diseased skin
We further evaluated whether our Th1/Th17-bearing psoriatic HSC (pHSC) were responsive to psoriasis drugs
To further validate Th1/Th17-bearing pHSCs as a psoriatic inflammation model, we examined whether the psoriatic phenotype in our human 3D skin constructs (HSCs) model could be reversed by other classes of drugs, such as recently discovered small molecules and cytokine targeting drugs, which are used clinically to inhibit specific targets involved in disease etiology

Summary

Introduction

Drug screening studies for inflammatory skin diseases are currently performed using model systems that only partially recapitulate human diseased skin. These cytokines alter epidermal proliferation and differentiation[12,13], and activate keratinocytes to release chemokines and chemoattractants, which induce further recruitment and infiltration of inflammatory cells into the skin[11] This complex feedback loop between keratinocytes and immune cells is central in the pathogenesis of psoriasis, current in vitro models do not capture these cellular interactions, such as migration of the immune cells, highlighting the need for an advanced model that recapitulates the physiological and immunological complexity of the disease. Our study establishes an advanced approach to recapitulate inflammatory skin diseases using patient-specific cells and a physiological in vitro platform that allows for dissecting epidermal and immune cell interactions as well as quantification of T cell migration into the skin in the context of disease progression and drug treatment

Methods

Results

Conclusion