Natural Tr1-like cells do not confer long-term tolerogenic memory.

Koshika Yadava,James J Moon,Ievgen O Koliesnik,Carlos Obed Medina,Elya Ali Shamskhou,Irina Gurevich,Kari Christine Nadeau,Paul L Bollyky,Heather Ishak,Hedwich Kuipers,Casey Weaver

doi:10.7554/elife.44821

Abstract

IL-10-producing Tr1 cells promote tolerance but their contributions to tolerogenic memory are unclear. Using 10BiT mice that carry a Foxp3-eGFP reporter and stably express CD90.1 following IL-10 production, we characterized the spatiotemporal dynamics of Tr1 cells in a house dust mite model of allergic airway inflammation. CD90.1+Foxp3-IL-10+ Tr1 cells arise from memory cells and rejoin the tissue-resident memory T-cell pool after cessation of IL-10 production. Persistent antigenic stimulation is necessary to sustain IL-10 production and Irf1 and Batf expression distinguishes CD90.1+Foxp3-IL-10+ Tr1 cells from CD90.1+Foxp3-IL-10- 'former' Tr1. Depletion of Tr1-like cells after primary sensitization exacerbates allergic airway inflammation. However, neither transfer nor depletion of former Tr1 cells influences either Tr1 numbers or the inflammatory response during subsequent allergen memory re-challenge weeks later. Together these data suggest that naturally-arising Tr1 cells do not necessarily give rise to more Tr1 upon allergen re-challenge or contribute to tolerogenic memory. This phenotypic instability may limit efforts to re-establish tolerance by expanding Tr1 in vivo.

Highlights

Allergic asthma is a common childhood illness and can be triggered by exposure to aeroallergens such as house dust mite (HDM)
IL-10-producing T cells accumulate at site of allergen sensitization
Animals are sensitized to crude house dust mite (HDM) protein intranasally (i.n.) over 2 weeks while control animals are given phosphate buffered saline (PBS)

Summary

Introduction

Allergic asthma is a common childhood illness and can be triggered by exposure to aeroallergens such as house dust mite (HDM). Hallmark features of the disease include aberrant T helper 2 (Th2) type responses, airway hyperreactivity, eosinophilic inflammation, increased IgE and mucus hypersecretion (Finkelman et al, 2010). The balance between pro-inflammatory CD4+ Th2 cells and regulatory T cells, including CD4 +Foxp3+ regulatory T cells (Treg) and CD4+Foxp3-, interleukin-10 (IL-10)-producing Type one regulatory T cells (Tr1) cells, is a significant determinant in the development of allergic disease (Robinson, 2009). Allergen-specific immunotherapy may re-establish tolerance in part by expanding these regulatory T cell populations (Akdis and Akdis, 2014; Meiler et al, 2008).

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