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 5

FcγRIII+ CD8+ T cells include canonical αβ and unconventional γδ T cell populations.

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FcγRIII+ CD8+ T cells include canonical αβ and unconventional γδ T cell ...
(A–G) Immunophenotypes in cord blood from cCMV-infected (n = 8, circles) versus uninfected (n = 8, diamonds) neonates. (A and B) CITRUS cluster map with gray outlines and shaded areas indicating immune cell clusters that differed significantly (FDR P < 0.01) between groups. Clusters colored by CD8+ T cells (purple, plum shade for increased FcγRIII expression), CD4+ T cells (red), NK cells (green), and non-T/NK cells (yellow, aqua) based on marker expression (NK T CITRUS in the Supplemental Material). (B) Expression of γδ TCR with black outlines showing FcγRIII+ CD8+ T cell clusters. (C) FcγRIII+ CD8+ T cell clusters (arrows in panel A). Dot plots indicate cluster abundance in cord blood from cCMV+ (red) versus cCMV– (blue) neonates. Histograms indicate fluorescent marker expression of select cluster (pink) relative to background (blue). (D and E) γδ T cells in cord blood from cCMV+ (red) versus cCMV– (blue) neonates. (D) Frequency of total γδ T cells and (E) γδ T cells expressing CD8/CD4 and FcγRIII. (F) Expression of αβ and γδ TCR and (G) differentiation/functional markers (F) on FcγRIII– (cCMV+ purple; cCMV– blue) and FcγRIII+ (plum) CD8+ T cells. FDR-corrected P values for Mann-Whitney U test (D and E) and ANOVA followed by Tukey’s post hoc test (F and G). *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.