SIV-induced terminally differentiated adaptive NK cells in lymph nodes associated with enhanced MHC-E restricted activity

Nicolas Huot,Christina M Stürzel,R Keith Reeves,Ulrike Sauermann,Jacob Nattermann,Hugo Varet,Rachel Legendre,Asier Sáez‐Cirión ,Roger Le Grand,Justin Harper ,Caroline Passaes,Frank Kirchhoff,Yoann Madec,Christiane Stahl–Hennig∥ ,Vanessa Contreras,Béatrice Jacquelin ,Caroline Petitdemange,Philippe Rascle,Eduard Baquero,Mirko Paiardini,Michaela Müller‐Trutwin

doi:10.1038/s41467-021-21402-1

Abstract

Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2alow NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. Adaptive NK cells displayed no increased NKG2C expression. This study reveals a previously unknown profile of NK cell adaptation to a viral infection, thus accelerating strategies toward NK-cell directed therapies and viral control in tissues.

Highlights

Natural killer (NK) cells play a critical understudied role during HIV infection in tissues
We addressed the question of the overall anti-viral activity profiles in the NK cells which expanded in lymph nodes (LN) upon acute (CXCR5+, NKG2a/clowCD16+) and/or chronic SIVagm infection (CXCR5+, NKG2a/clowCD16−) using the genome-wide expression data (Fig. 5)
We designed a study comparing NK cells associated with a strong viral control in secondary lymphoid tissues (SLT) (SIVagm infection) to NK cells lacking the capacity of an efficient viral control (SIVmac infection)

Summary

Introduction

Natural killer (NK) cells play a critical understudied role during HIV infection in tissues. In a natural host of SIV, the African green monkey (AGM), NK cells mediate a strong control of SIVagm infection in secondary lymphoid tissues. We demonstrate that SIVagm infection induces the expansion of terminally differentiated NKG2alow NK cells in secondary lymphoid organs displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides while expressing little IFN-γ. Such NK cell differentiation was lacking in SIVmac-infected macaques. We show that SIVagm infection induces the expansion of terminally differentiated NKG2alow NK cells in SLT displaying an adaptive transcriptional profile and increased MHC-E-restricted cytotoxicity in response to SIV Env peptides. It improves our understanding of NK cell dysfunction in HIV infection and thereby opens avenues to improve NK-cell mediated viral control in HIV cure strategies

Methods

Results

Conclusion