The ubiquitin ligase Peli1 inhibits ICOS and thereby Tfh-mediated immunity

Xinfang Huang,Tao Yu,Siyu Pei,Junli Liu,Shumeng Hao,Yuanyuan Huang,Manman Liu,Dongfang Dai,Yan Wang,Xiao Su,Jing Xu,Yichuan Xiao,Haikun Wang,Chunyuan Xiao

doi:10.1038/s41423-021-00660-5

Abstract

T follicular helper (Tfh) cells are crucial for regulating autoimmune inflammation and protective immunity against viral infection. However, the molecular mechanism controlling Tfh cell differentiation is poorly understood. Here, through two mixed bone marrow chimeric experiments, we identified Peli1, a T cell-enriched E3 ubiquitin ligase, as an intrinsic regulator that inhibits Tfh cell differentiation. Peli1 deficiency significantly promoted c-Rel-mediated inducible T-cell costimulator (ICOS) expression, and PELI1 mRNA expression was negatively associated with ICOS expression on human CD4+ T cells. Mechanistically, increased ICOS expression on Peli1-KO CD4+ T cells enhanced the activation of PI3K-AKT signaling and thus suppressed the expression of Klf2, a transcription factor that inhibits Tfh differentiation. Therefore, reconstitution of Klf2 abolished the differences in Tfh differentiation and germinal center reaction between WT and Peli1-KO cells. As a consequence, Peli1-deficient CD4+ T cells promoted lupus-like autoimmunity but protected against H1N1 influenza virus infection in mouse models. Collectively, our findings established Peli1 as a critical negative regulator of Tfh differentiation and indicated that targeting Peli1 may have beneficial therapeutic effects in Tfh-related autoimmunity or infectious diseases.

Highlights

T follicular helper (Tfh) cells are a subset of CD4+ T cells that develop in B-cell follicles, where they interact with and assist B lymphocytes in germinal center (GC) formation.[1,2,3] Upon interaction with B cells, Tfh cells promote the activation and induction of GC B cells, which is required for the terminal differentiation of these cells into long-lived plasma cells to produce antigenspecific, high-affinity antibodies.[2,3] Tfh cells play an essential role in protective immunity against infection by various pathogens, such as influenza virus
Peli[1] intrinsically inhibits Tfh differentiation To investigate whether Peli[1] regulates Tfh cell differentiation, we adoptively transferred WT or Peli1-deficient naive CD4+ T cells mixed with WT B cells into Rag1-knockout (KO) mice, which were immunized with nitrophenol-keyhole limpet hemocyanin (NP-KLH) to induce the generation of Tfh cells in vivo
To determine whether Peli1-mediated regulation of Tfh cell differentiation is T cell intrinsic, we generated mixed bone marrow (BM) chimeras in lethally irradiated Rag1-KO mice by reconstitution with a mixture of 50% BM from SJL mice and 50% BM from WT or Peli1-KO mice, and these chimeric mice were immunized with NP-KLH 8 weeks post BM reconstitution (Fig. 1C)

Summary

Introduction

T follicular helper (Tfh) cells are a subset of CD4+ T cells that develop in B-cell follicles, where they interact with and assist B lymphocytes in germinal center (GC) formation.[1,2,3] Upon interaction with B cells, Tfh cells promote the activation and induction of GC B cells, which is required for the terminal differentiation of these cells into long-lived plasma cells to produce antigenspecific, high-affinity antibodies.[2,3] Tfh cells play an essential role in protective immunity against infection by various pathogens, such as influenza virus. We identified Peli[1] as a pivotal negative regulator that inhibits T-cell activation and in vivo autoimmunity by modulating the K48-linked ubiquitination and degradation of c-Rel.[10] More recently, a published study demonstrated that a microRNA, miR-155, is required for the generation and function of Tfh cells through targeting Peli[1] and showed that heterozygous deletion of Peli[1] in miR-155−/− T cells substantially rescued impaired Tfh generation, suggesting a potential role of Peli[1] in Tfh cells.[11] whether and how Peli[1] modulates Tfh cell differentiation and related biological functions remain undetermined. Deletion of Peli[1] promotes Tfh-mediated antibody production in vivo, which promotes lupus-like disease but prevents influenza virus infection

Methods

Results

Conclusion