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 3

CD8+ T cells upregulate cytotoxicity and NK cell genes in cord blood from cCMV-infected neonates.

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CD8+ T cells upregulate cytotoxicity and NK cell genes in cord blood fro...
(A and B) CD8+ T cell immunophenotypes were compared in cord blood from cCMV-infected (cCMV+, red circles, n = 21) versus cCMV-uninfected (cCMV–, blue diamonds, n = 20) neonates. (A and B) Frequency of total, naive, Tcm, Tem, and Temra CD8+ T cells. (C) Frequency of CD8+ T cells expressing HLA-DR, CD57, and PD-1 in cCMV+ (n = 8) versus cCMV– (n = 8) neonates. (D–G) RNA-Seq analysis of FAC-sorted total CD8+ T cells from cCMV+ (n = 13) and cCMV– (n = 11) neonates. (D) Volcano plot demonstrating differentially expressed genes (P < 0.01, log2foldchange +/– 1.2). Red circles indicate genes enriched in cCMV+, blue circles indicate genes enriched in cCMV–, and gray circles indicate genes whose expression did not differ significantly. (E) Heatmap of top 40 enriched genes (FDR P < 0.1, log2foldchange > 3.0). (F and G) Expression of genes encoding (F) cytolytic molecules and (G) NK-associated cell markers. z score shows gene expression based on rlog-transformed data. FDR-corrected P values for Mann-Whitney U test. *P < 0.05; **P < 0.01; ***P < 0.001.