Tox2 is required for the maintenance of GC TFH cells and the generation of memory TFH cells.

Shu Horiuchi,Wen-Chun Liu,Salah-Eddine Bentebibel,Hanchih Wu,Yang Liu,Hideki Ueno,Bin Zhang,Michael Schotsaert,Nathalie Schmitt,Randy A Albrecht,Jonathan Provot,Christian V Forst

doi:10.1126/sciadv.abj1249

Abstract

Memory T follicular helper (TFH) cells play an essential role to induce secondary antibody response by providing help to memory and naïve B cells. Here, we show that the transcription factor Tox2 is vital for the maintenance of TFH cells in germinal centers (GCs) and the generation of memory TFH cells. High Tox2 expression was almost exclusive to GC TFH cells among human tonsillar and blood CD4+ T cell subsets. Tox2 overexpression maintained the expression of TFH-associated genes in T cell receptor–stimulated human GC TFH cells and inhibited their spontaneous conversion into TH1-like cells. Tox2-deficient mice displayed impaired secondary TFH cell expansion upon reimmunization with an antigen and upon secondary infection with a heterologous influenza virus. Collectively, our study shows that Tox2 is highly integrated into establishment of durable GC TFH cell responses and development of memory TFH cells in mice and humans.

Highlights

Immunological memory is fundamental to protect the host from a reinfection of the pathogen
The expression of TOX2 in tonsillar CD4+ T cell subsets showed a positive correlation with CXCR5, ICOS, and PD1 in a protein level (Fig. 1D), and TOX2 expression showed a positive correlation with mRNA expression of T follicular helper (TFH)-associated genes including PDCD1, BCL6, IL21, MAF, Horiuchi et al, Sci
Mock-transfected germinal centers (GCs) TFH and PreTFH cells expressed more IFN, but not IL-4, upon polyclonal stimulation than Tox2- transfected cells (Fig. 3C). These results indicate that Tox2 insulates T cell receptor (TCR)-stimulated GC TFH cells from becoming T helper 1 (TH1)-like cells

Summary

Introduction

Immunological memory is fundamental to protect the host from a reinfection of the pathogen. The maintenance of humoral memory is mediated by long-lived plasma cells and memory B cells [1] Their development requires helper signals, including CD40, provided by T follicular helper (TFH) cells in germinal centers (GCs) [2,3,4]. Memory TFH cells remain in lymphoid organs as local memory TFH cells [17], and current evidence shows that memory TFH cells can be derived from mature GC TFH cells and T cells committed to the TFH lineage yet not fully mature The latter pathway is evident by the observation that animals deficient of functional stress-activated protein [SLAM-associated protein (SAP)], which lack the development of GC TFH cells, can still generate memory cTFH cells [16]. Vaccinia virus–specific cTFH cells can remain for decades after the vaccination [19], an observation indicating their persistence without

Methods

Results

Conclusion