Effector CD4+ T cells recognize intravascular antigen presented by patrolling monocytes

Clare L V Westhorpe,M Ursula Norman,Sarah L Snelgrove,Susan K Nilsson,Michaela Finsterbusch,Pam Hall,Zhe Hao Tan,Michael J Hickey,Songhui Li,A Richard Kitching,Camden Lo,Anqi Li

doi:10.1038/s41467-018-03181-4

Abstract

Although effector CD4+ T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown. Here we show the process of intravascular antigen recognition using intravital multiphoton microscopy of glomeruli. CD4+ T cells undergo intravascular migration within uninflamed glomeruli. Similarly, while MHCII is not expressed by intrinsic glomerular cells, intravascular MHCII-expressing immune cells patrol glomerular capillaries, interacting with CD4+ T cells. Following intravascular deposition of antigen in glomeruli, effector CD4+ T-cell responses, including NFAT1 nuclear translocation and decreased migration, are consistent with antigen recognition. Of the MHCII+ immune cells adherent in glomerular capillaries, only monocytes are retained for prolonged durations. These cells can also induce T-cell proliferation in vitro. Moreover, monocyte depletion reduces CD4+ T-cell-dependent glomerular inflammation. These findings indicate that MHCII+ monocytes patrolling the glomerular microvasculature can present intravascular antigen to CD4+ T cells within glomerular capillaries, leading to antigen-dependent inflammation.

Highlights

1,6, Anqi Li1, effector CD4+ T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown
CD4+ T cells specific for nephritogenic autoantigens are present in the circulation during autoimmune glomerulonephritis[26,27,28], and experimental evidence indicates that CD4+ T-cell-dependent glomerular inflammation can be initiated by T cells responding to antigen located within the vasculature[15,16]
The present study addresses this by demonstrating that the cellular participants required for a CD4+ T-cell-mediated response—CD4+ T cells and an MHC class II (MHCII)-expressing cell—both undergo constitutive periods of intravascular retention and crawling in the glomerular microvasculature

Summary

Introduction

1,6, Anqi Li1, effector CD4+ T cells readily respond to antigen outside the vasculature, how they respond to intravascular antigens is unknown. Patrolling Ly6C− monocytes perform important immune surveillance within the vasculature, internalizing microparticles and soluble material from the bloodstream and responding to microbial infection or tissue injury[3,7] Upon detection of these signals, intravascular monocytes are positioned to respond rapidly by inducing recruitment of other immune cells or migrating out of the vasculature[3,4,5]. These intravascular activities are not restricted to myeloid leukocytes as in the liver microvasculature, invariant natural killer T (iNKT) cells constitutively migrate. Some endothelial cells can express MHC class II (MHCII) in inflammatory states, mechanisms of antigen recognition by antigen-specific CD4+ T cells within the vasculature are unclear[15,16,17]

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