The HVEM-BTLA Axis Restrains T Cell Help to Germinal Center B Cells and Functions as a Cell-Extrinsic Suppressor in Lymphomagenesis

Michelle A Mintz,James H Felce,Marissa Y Chou,Viveka Mayya,Ying Xu,Jr-Wen Shui,Jinping An,Zhongmei Li,Alexander Marson,Takaharu Okada,Carl F Ware,Mitchell Kronenberg,Michael L Dustin,Jason G Cyster

doi:10.1016/j.immuni.2019.05.022

Abstract

SummaryThe tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.

Highlights

High-affinity germinal center (GC)-derived antibodies are crucial for protection from many pathogens
HVEM Deficiency Increases GC B Cell Competitiveness Hvem (Tnfrsf14) transcripts were expressed at similar levels in follicular and GC B cells (Figure 1A), and HVEM was present on the surface of both cell types, though at lower levels on GC B cells (Figure 1B)
To test whether HVEM is an intrinsic regulator of GC B cell responses, we generated mixed-bone-marrow (BM) chimeric mice where BM from wild-type (WT) CD45.1 donor mice was mixed with CD45.2 BM from Hvem+/À or HvemÀ/À mice

Summary

Introduction

High-affinity germinal center (GC)-derived antibodies are crucial for protection from many pathogens. During a T-cell-dependent response, antigen-reactive B cells are selected for entry into the GC by CD4+ T cells. The earliest T cell selection of the B cell occurs at the T-B border 1–2 days after antigen exposure. After 3–6 days, T cells residing in the GC, termed T follicular helper (Tfh) cells, are required to select GC B cells. Most data favor a model for high-affinity B cell selection where cells with improved affinity internalize and present more of the antigen and win out in receiving more or better-quality T cell help through CD40 ligand (CD40L) or other signals (Bannard and Cyster, 2017; Mesin et al, 2016). Which factors beyond major histocompatibility complex (MHC) class II-peptide amounts determine the quantity and quality of help delivered to GC B cells is incompletely understood

Results

Discussion

Conclusion