(Auto)Antibody Responses Shape Memory NK Cell Pool Size and Composition.

Cristina Capuano,Davide De Federicis,Giuseppe Sciumè,Cristina Santoro,Gabriella Palmieri,Ricciarda Galandrini,Chiara Pighi,Antonietta Ferretti,Fabio Pulcinelli,Ombretta Turriziani,Cinzia Fionda,Simone Battella

doi:10.3390/biomedicines10030625

Cristina Capuano, Davide De Federicis + Show 10 more

Open Access

https://doi.org/10.3390/biomedicines10030625

Copy DOI

Journal: Biomedicines	Publication Date: Mar 8, 2022
Citations: 1	License type: CC BY 4.0

Affiliation: Sapienza University of Rome, Policlinico Umberto I

Abstract

In vivo establishment and long-term persistence of a heterogeneous memory or an adaptive NK cell pool represents a functional adaptation to human cytomegalovirus (HCMV) infection in humans. Memory NK cells are commonly identified by lack of the FcεRIγ signalling chain, variably associated to the preferential but not completely overlapping expression of the HLA-E receptor NKG2C and CD57 maturation marker. Although characterized by selective hyperresponsiveness to IgG stimulation, the impact of the CD16/antibody interaction in regulating the establishment/maintenance and size, and in determining the relative abundance of this population, is still under investigation. Memory NK cell subset ex vivo profile and in vitro responsiveness to CD16 stimulation was evaluated in HCMV+ healthy donors and in patients affected by immune thrombocytopenia (ITP), an antibody-mediated autoimmune disease. We identified the FcεRIγ− NKG2C+CD57+ memory NK cell subset, whose abundance is uniquely associated with anti-HCMV antibody levels in healthy seropositive donors, and which is significantly expanded in ITP patients. This fully mature memory subset robustly and selectively expands in vitro in response to mAb-opsonized targets or ITP-derived platelets and displays superior CD16-dependent IFNγ production. Our work identifies opsonizing antibodies as a host-dependent factor that shapes HCMV-driven memory NK cell compartment. We first demonstrate that chronic exposure to auto-antibodies contributes to the establishment/expansion of a highly specialized and unique memory NK cell subset with distinct CD16-dependent functional capabilities. We also identify the specific contribution of the lack of FcεRIγ chain in conferring to NKG2C+CD57+ memory cells a higher responsivity to CD16 engagement.

Highlights

The spectrum of NK cell heterogeneity varies among individuals, reflecting in part their adaptation to pathogens
Memory NK cell subsets were analysed in human cytomegalovirus (HCMV)+ healthy subjects, and in patients affected by immune thrombocytopenia (ITP), an autoimmune condition characterized by platelet- and megakaryocyte-opsonizing antibodies [36]; importantly, we directly demonstrated that chronic exposure to ITP platelets drives the in vitro expansion of memory NK cell subsets
These observations confirm that HCMV-seropositivity sharply associates with the expansion of NKG2C and CD57 co-expressing cells and highlight that the absence of a FcεRIγ chain confers a significative advantage for their expansion/persistence in vivo

Summary

Introduction

The spectrum of NK cell heterogeneity varies among individuals, reflecting in part their adaptation to pathogens. A distinct but heterogeneous population of mature NK cells that exhibits adaptive immune features, which include the long-term persistence in vivo, a distinct epigenetic and metabolic profile resembling that of memory CD8+ T cells, and a peculiar equipment of intracellular enzymes and signalling components, has been described in a fraction of healthy HCMV+. Such “memory” or “adaptive” NK cells are marked by a functional hyperresponsivity to CD16 ( named FcγRIIIA), stimulation [5–8]. Their enhanced capability to produce IFNγ, TNFα, and chemokines upon CD16 stimulation is coupled to low responsiveness to NKp46 and NKp30 NCR engagement, as well as to IL-12/IL-18 inflammatory cytokines, as compared to conventional counterparts [7,9–11]. The memory NK cell pool, whose size greatly varies among HCMV+ individuals [12,13], has been identified within mature CD56dim CD16+ NK cells through the expression of variable and not completely overlapping combinations of markers; the epigenetically controlled downmodulation of an FcεRIγ signalling molecule on one side, and the preferential expression of NKG2C activating receptor and of CD57 maturation marker on the other, are most commonly employed [2,5,6,14–17]

Methods

Results

Conclusion