Hallmarks of primate lentiviral immunodeficiency infection recapitulate loss of innate lymphoid cells

Joseph C Mudd,Jason M Brenchley,Brian Richardson,Sarah R Dinapoli,Andrea Lisco,Mirko Paiardini,Jacob D Estes,David J Palesch,R Keith Reeves,Mark Cameron,Stephen Lai,Irini Sereti,Kathleen Busman-Sahay,Claire Deleage,Virginia Sheik

doi:10.1038/s41467-018-05528-3

Abstract

Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense and tissue homeostasis. While ILCs are depleted in HIV-1 infection, this phenomenon is not a generalized feature of all viral infections. Here we show in untreated SIV-infected rhesus macaques (RMs) that ILC3s are lost rapidly in mesenteric lymph nodes (MLNs), yet preserved in SIV+ RMs with pharmacologic or natural control of viremia. In healthy uninfected RMs, experimental depletion of CD4+ T cells in combination with dextran sodium sulfate (DSS) is sufficient to reduce ILC frequencies in the MLN. In this setting and in chronic SIV+ RMs, IL-7Rα chain expression diminishes on ILC3s in contrast to the IL-18Rα chain expression which remains stable. In HIV-uninfected patients with durable CD4+ T cell deficiency (deemed idiopathic CD4+ lymphopenia), similar ILC deficiencies in blood were observed, collectively identifying determinants of ILC homeostasis in primates and potential mechanisms underlying their depletion in HIV/SIV infection.

Highlights

Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense and tissue homeostasis
We found that lineage −IL7Rα+ ILCs constitute a small proportion of hematopoietic cells in the mesenteric lymph nodes (MLNs) and form distinct subpopulations that parallel those of humans and mice. c-Kit+NKp44− and c-Kit+NKp44+ ILC3s (Fig. 1a) could be found in MLNs and expressed elevated levels of the Th17/ILC3 lineage-promoting transcription factor RAR-related orphan receptor gamma (ROR-γt) (Fig. 1b)[14,24]
Chronic GI inflammation is a hallmark of HIV-1 and progressive simian immunodeficiency virus (SIV) infection[7], and recent evidence indicates that death of blood ILCs occurs early in HIV-1 disease course

Summary

Introduction

Innate lymphoid cells (ILCs) play critical roles in mucosal barrier defense and tissue homeostasis. Experimental GI damage in a chronic SIV-infected natural host model resulted in colitis, microbial translocation, inflammation, and CD4+ T cell depletion, all key pathologies resembling SIV-infected Asian macaques[5]. GI damage in SIV-infected Asian macaques and HIV-1-infected humans results in microbial translocation that chronically stimulates the immune system and exacerbates disease progression[6]. We find that ILC2 and ILC3 subtypes were lost throughout SIV disease course, yet were reconstituted or preserved with pharmacologic or natural control of viremia, respectively In both uninfected RMs experimentally depleted of CD4 T cells and human subjects with idiopathic CD4 lymphopenia (ICL), absence of CD4+ T cells alone was associated with severe ILC deficiencies, providing possible mechanisms of ILC loss in lentiviral immunodeficiency infections and identifying novel determinants of ILC homeostasis in health

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