Human cytomegalovirus elicits fetal γδ T cell responses in utero

The fetus and infant are highly susceptible to viral infections. Several viruses, including human cytomegalovirus (CMV), cause more severe disease in early life compared with later life. It is generally accepted that this is a result of the immaturity of the immune system. gamma delta T cells are unconventional T cells that can react rapidly upon activation and show major histocompatibility complex-unrestricted activity. We show that upon CMV infection in utero, fetal gamma delta T cells expand and become differentiated. The expansion was restricted to V gamma 9-negative gamma delta T cells, irrespective of their V delta chain expression. Differentiated gamma delta T cells expressed high levels of IFN-gamma, transcription factors T-bet and eomes, natural killer receptors, and cytotoxic mediators. CMV infection induced a striking enrichment of a public V gamma 8V delta 1-TCR, containing the germline-encoded complementary-determining-region-3 (CDR3)delta 1-CALGELGDDKLIF/CDR3 gamma 8-CATWDTTGWFKIF. Public V gamma 8V delta 1-TCR-expressing cell clones produced IFN-gamma upon coincubation with CMV-infected target cells in a TCR/CD3-dependent manner and showed antiviral activity. Differentiated gamma delta T cells and public V gamma 8V delta 1-TCR were detected as early as after 21 wk of gestation. Our results indicate that functional fetal gamma delta T cell responses can be generated during development in utero and suggest that this T cell subset could participate in antiviral defense in early life.