Btn2a2 Regulates ILC2-T Cell Cross Talk in Type 2 Immune Responses.

Michael Frech,Angelika Schmalzl,Stefan Wirtz,Mario M Zaiss,Yasunori Omata,Kerstin Sarter,Leila Taher,Georg Schett

doi:10.3389/fimmu.2022.757436

Abstract

Innate lymphoid cells (ILC) not only are responsible for shaping the innate immune response but also actively modulate T cell responses. However, the molecular processes regulating ILC-T cell interaction are not yet completely understood. The protein butyrophilin 2a2 (Btn2a2), a co-stimulatory molecule first identified on antigen-presenting cells, has a pivotal role in the maintenance of T cell homeostasis, but the main effector cell and the respective ligands remain elusive. We analyzed the role of Btn2a2 in the ILC-T cell cross talk. We found that the expression of Btn2a2 is upregulated in ILC2 following stimulation with IL-33/IL-25/TSLP. In vitro and in vivo experiments indicated that lack of Btn2a2 expression on ILC2 resulted in elevated T cell responses. We observed an enhanced proliferation of T cells as well as increased secretion of the type 2 cytokines IL-4/IL-5/IL-13 following cocultures with Btn2a2-deficient ILC2. In vivo transfer experiments confirmed the regulatory role of Btn2a2 on ILC2 as Btn2a2-deficient ILC2 induced stronger T cell responses and prevented chronic helminth infections. Taken together, we identified Btn2a2 as a significant player in the regulation of ILC2–T cell interactions.

Highlights

Innate lymphoid cells (ILC) were shown to play a role in modulating adaptive T cell responses
Our findings indicate a critical role of the co-stimulatory molecule butyrophilin 2a2 (Btn2a2) in the regulation of the ILC2-T cell cross talk during inflammatory type 2 responses
ILC2 and Th2 cells interact on multiple levels, ILC2 regulate CD4+ T cell responses and in turn receive feedback from these cells during the ILC2 T cell cross talk

Summary

Introduction

Innate lymphoid cells (ILC) were shown to play a role in modulating adaptive T cell responses. Addition of unchallenged ILC2 that were not exogenously stimulated with IL-33 to naïve CD4+ T cells induces their differentiation into Th2 cells and inhibits differentiation into Th1 cells [8]. In line with these findings, type 2 cytokines are not detectable if CD4+ T cells are cultured with ILC2 unable to secrete IL-4 [9]. Taken together, these studies show that ILC2-derived IL-4 contributes to the induction of Th2 response; an IL-4independent pathway may exist [6]. It is still widely believed that ILC activity is based on their

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