DOCK8 is essential for LFA-1-dependent positioning of T follicular helper cells in germinal centers.

Erin Janssen,Salem Al-Tamemi,Sophie Giguere,Peter T Sage,Mrinmoy Das,Raif S Geha,Facundo Batista,Francisco E Velázquez,Ali Sobh,Jordan Butts,Christy Kam,Francis W Luscinskas,Mira Tohme,Elena Milin

doi:10.1172/jci.insight.134508

Abstract

T follicular helper (Tfh) cell migration into germinal centers (GCs) is essential for the generation of GC B cells and antibody responses to T cell-dependent (TD) antigens. This process requires interactions between lymphocyte function-associated antigen 1 (LFA-1) on Tfh cells and ICAMs on B cells. The mechanisms underlying defective antibody responses to TD antigens in DOCK8 deficiency are incompletely understood. We show that mice selectively lacking DOCK8 in T cells had impaired IgG antibody responses to TD antigens, decreased GC size, and reduced numbers of GC B cells. However, they developed normal numbers of Tfh cells with intact capacity for driving B cell differentiation into a GC phenotype in vitro. Notably, migration of DOCK8-deficient T cells into GCs was defective. Following T cell receptor (TCR)/CD3 ligation, DOCK8-deficient T cells had impaired LFA-1 activation and reduced binding to ICAM-1. Our results therefore indicate that DOCK8 is important for LFA-1-dependent positioning of Tfh cells in GCs, and thereby the generation of GC B cells and IgG antibody responses to TD antigen.

Highlights

The antibody response to T cell–dependent (TD) antigens requires interactions between T follicular helper (Tfh) cells and B cells
We show that mice with selective DOCK8 deficiency in T cells mount poor IgG antibody responses to TD antigens, and have impaired germinal centers (GCs) formation and reduced numbers of GC B cells despite normal numbers of Tfh cells that are able to normally drive B cell differentiation in vitro
Using a monoclonal antibody that selectively recognizes the active conformation of LFA1 on human cells, we examined the ability of T cells from DOCK8-deficient patients with homozygous DOCK8 mutations that abrogated protein expression to activate lymphocyte function–associated antigen 1 (LFA-1) following T cell receptor (TCR)/CD3 ligation

Summary

Introduction

The antibody response to T cell–dependent (TD) antigens requires interactions between T follicular helper (Tfh) cells and B cells. Activated T cells migrate toward the B cell follicle, where they interact with B cells This leads to the expression of Tfh cell–specific markers [2], including ICOS and programmed cell death 1 (PD-1) [3,4,5]. Tfh cell production of IL-4 and IL-21, as well as the interaction between CD40L on Tfh cells and CD40 on B cells, are important for GC B cell proliferation, differentiation, BCL6 expression, and survival [13,14,15]. We show that mice with selective DOCK8 deficiency in T cells mount poor IgG antibody responses to TD antigens, and have impaired GC formation and reduced numbers of GC B cells despite normal numbers of Tfh cells that are able to normally drive B cell differentiation in vitro. We demonstrate that activated DOCK8-deficient T cells have impaired LFA-1 activation and defective migration into GCs

Results

Discussion

Methods