Hypercytotoxicity and Rapid Loss of NKp44+ Innate Lymphoid Cells during Acute SIV Infection

PLoS Pathogens

Jacob D. Estes¹  Brandon F. Keele¹  Haiying Li²  R. Keith Reeves²  Laura E. Richert-Spuhler³  Nichole R. Klatt³  Michelle Connole⁴  Jacqueline Gillis⁴  Tristan I. Evans⁴ 

[1] AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory, Frederick, Maryland, United States of America;Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States of America;Department of Pharmaceutics, Washington National Primate Research Center, University of Washington, Seattle, Washington, United States of America;Division of Immunology, New England Primate Research Center, Harvard Medical School, Southborough Campus, Southborough, Massachusetts, United States of America

关键词: Macaque;    NK cells;    SIV;    Cloning;    Genitourinary infections;    Cytokines;    Gastrointestinal infections;    Gastrointestinal tract;   

DOI  :  10.1371/journal.ppat.1004551

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

HIV/SIV infections break down the integrity of the gastrointestinal mucosa and lead to chronic immune activation and associated disease progression. Innate lymphoid cells (ILCs), distinguishable by high expression of NKp44 and RORγt, play key roles in mucosal defense and homeostasis, but are depleted from gastrointestinal (GI) tract large bowel during chronic SIV infection. However, less is known about the kinetics of ILC loss, or if it occurs systemically. In acute SIV infection, we found a massive, up to 8-fold, loss of NKp44+ILCs in all mucosae as early as day 6 post-infection, which was sustained through chronic disease. Interestingly, no loss of ILCs was observed in mucosa-draining lymph nodes. In contrast, classical NK cells were not depleted either from gut or draining lymph nodes. Both ILCs and NK cells exhibited significantly increased levels of apoptosis as measured by increased Annexin-V expression, but while classical NK cells also showed increased proliferation, ILCs did not. Interestingly, ILCs, which are normally noncytolytic, dramatically upregulated cytotoxic functions in acute and chronic infection and acquired a polyfunctional phenotype secreting IFN-γ, MIP1-β, and TNF-α, but decreased production of the prototypical cytokine, IL-17. Classical NK cells had less dramatic functional change, but upregulated perforin expression and increased cytotoxic potential. Finally, we show that numerical and functional loss of ILCs was due to increased apoptosis and ROR γt suppression induced by inflammatory cytokines in the gut milieu. Herein we demonstrate the first evidence for acute, systemic, and permanent loss of mucosal ILCs during SIV infection associated with reduction of IL-17. The massive reduction of ILCs involves apoptosis without compensatory de novo development/proliferation, but the full mechanism of depletion and the impact of functional change so early in infection remain unclear.

【 授权许可】

CC BY