In utero human cytomegalovirus infection expands NK-like FcγRIII+CD8+ T cells that mediate Fc antibody functions
Eleanor C. Semmes, Danielle R. Nettere, Ashley N. Nelson, Jillian H. Hurst, Derek W. Cain, Trevor D. Burt, Joanne Kurtzberg, R. Keith Reeves, Carolyn B. Coyne, Genevieve G. Fouda, Justin Pollara, Sallie R. Permar, Kyle M. Walsh
Eleanor C. Semmes, Danielle R. Nettere, Ashley N. Nelson, Jillian H. Hurst, Derek W. Cain, Trevor D. Burt, Joanne Kurtzberg, R. Keith Reeves, Carolyn B. Coyne, Genevieve G. Fouda, Justin Pollara, Sallie R. Permar, Kyle M. Walsh
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Research Article Immunology Infectious disease

In utero human cytomegalovirus infection expands NK-like FcγRIII+CD8+ T cells that mediate Fc antibody functions

Abstract

Human cytomegalovirus (HCMV) profoundly impacts host T and NK cells across the lifespan, yet how this common congenital infection modulates developing fetal immune cell compartments remains underexplored. Using cord blood from neonates with and without congenital HCMV (cCMV) infection, we identify an expansion of Fcγ receptor III–expressing (FcγRIII-expressing) CD8+ T cells following HCMV exposure in utero. Most FcγRIII+CD8+ T cells express the canonical αβ T cell receptor (TCR), but a proportion express noncanonical γδ TCR. FcγRIII+CD8+ T cells are highly differentiated and have increased expression of NK cell markers and cytolytic molecules. Transcriptional analysis reveals FcγRIII+CD8+ T cells upregulate T-bet and downregulate BCL11B, known transcription factors that govern T/NK cell fate. We show that FcγRIII+CD8+ T cells mediate antibody-dependent IFN-γ production and degranulation against IgG-opsonized target cells, similar to NK cell antibody-dependent cellular cytotoxicity (ADCC). FcγRIII+CD8+ T cell Fc effector functions were further enhanced by IL-15, as has been observed in neonatal NK cells. Our study reveals that FcγRIII+CD8+ T cells elicited in utero by HCMV infection can execute Fc-mediated effector functions bridging cellular and humoral immunity and may be a promising target for antibody-based therapeutics and vaccination in early life.

Authors

Eleanor C. Semmes, Danielle R. Nettere, Ashley N. Nelson, Jillian H. Hurst, Derek W. Cain, Trevor D. Burt, Joanne Kurtzberg, R. Keith Reeves, Carolyn B. Coyne, Genevieve G. Fouda, Justin Pollara, Sallie R. Permar, Kyle M. Walsh

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Figure 4

CD8+ T cells expressing NK cell receptors FcγRIII and NKG2A/C expand in cord blood from cCMV-infected neonates.

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CD8+ T cells expressing NK cell receptors FcγRIII and NKG2A/C expand in ...
(A–D) CITRUS analysis of flow cytometry data was used to identify immune cell populations with differing abundance in cord blood from cCMV-infected (n = 13) versus cCMV-uninfected (n = 12) neonates. (A) t-SNE-CUDA dimensionality reduction of flow cytometry data prior to CITRUS. (B) CITRUS cluster map with black outlines and shaded areas indicating clusters that differed significantly (FDR P < 0.01) between cCMV+ and cCMV– groups. Clusters colored by CD8+ T cells (purple), CD4+ T cells (red), NK cells (green), B cells (yellow), monocytes/macrophages (MO/Mϕ; orange) and dendritic cells (DCs; blue) based on marker expression (General Lineage CITRUS in the Supplemental Material). (C and D) Select clusters (black arrows in panel B) of CD8+ T cells expressing NK cell markers. Dot plots indicate cluster abundance in cCMV+ (red circles) versus cCMV– (blue circles) neonates. Histograms indicate fluorescent marker expression of select cluster (pink) relative to background (blue). (E) Gating strategy to identify CD8+ T cells expressing NK cell markers. (F) Frequency of FcγRIII and NKG2A/C expression on CD8+ T cells from cCMV+ (red circles, n = 21) versus cCMV– (blue diamonds, n = 20) neonates. FDR-corrected P values for Mann-Whitney U test. ***P < 0.001.