Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection

Haiying Li, Laura E. Richert-Spuhler, Tristan I. Evans, Jacqueline Gillis, Michelle Connole, Jacob Estes, Brandon F. Keele, Nichole R. Klatt, R. Keith Reeves

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)e1004551
JournalPLoS Pathogens
Volume10
Issue number12
DOIs
StatePublished - Dec 1 2014
Externally publishedYes

Fingerprint

Lymphocytes
Infection
Natural Killer Cells
Mucous Membrane
Interleukin-17
Apoptosis
Lymph Nodes
Cytokines
Perforin
Annexin A5
HIV Infections
Disease Progression
Gastrointestinal Tract
Homeostasis
Chronic Disease
Phenotype

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Molecular Biology
  • Genetics
  • Virology

Cite this

Li, H., Richert-Spuhler, L. E., Evans, T. I., Gillis, J., Connole, M., Estes, J., ... Reeves, R. K. (2014). Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. PLoS Pathogens, 10(12), e1004551. https://doi.org/10.1371/journal.ppat.1004551

Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. / Li, Haiying; Richert-Spuhler, Laura E.; Evans, Tristan I.; Gillis, Jacqueline; Connole, Michelle; Estes, Jacob; Keele, Brandon F.; Klatt, Nichole R.; Reeves, R. Keith.

In: PLoS Pathogens, Vol. 10, No. 12, 01.12.2014, p. e1004551.

Research output: Contribution to journalArticle

Li, H, Richert-Spuhler, LE, Evans, TI, Gillis, J, Connole, M, Estes, J, Keele, BF, Klatt, NR & Reeves, RK 2014, 'Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection', PLoS Pathogens, vol. 10, no. 12, pp. e1004551. https://doi.org/10.1371/journal.ppat.1004551
Li, Haiying ; Richert-Spuhler, Laura E. ; Evans, Tristan I. ; Gillis, Jacqueline ; Connole, Michelle ; Estes, Jacob ; Keele, Brandon F. ; Klatt, Nichole R. ; Reeves, R. Keith. / Hypercytotoxicity and rapid loss of NKp44+ innate lymphoid cells during acute SIV infection. In: PLoS Pathogens. 2014 ; Vol. 10, No. 12. pp. e1004551.
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