Human cytomegalovirus elicits fetal γδ T cell responses in utero

Abstract

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. γδ 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 γδ T cells expand and become differentiated. The expansion was restricted to Vγ9-negative γδ T cells, irrespective of their Vδ chain expression. Differentiated γδ T cells expressed high levels of IFN-γ, transcription factors T-bet and eomes, natural killer receptors, and cytotoxic mediators. CMV infection induced a striking enrichment of a public Vγ8Vδ1-TCR, containing the germline-encoded complementary-determining-region-3 (CDR3) δ1–CALGELGDDKLIF/CDR3γ8–CATWDTTGWFKIF. Public Vγ8Vδ1-TCR–expressing cell clones produced IFN-γ upon coincubation with CMV-infected target cells in a TCR/CD3-dependent manner and showed antiviral activity. Differentiated γδ T cells and public Vγ8Vδ1-TCR were detected as early as after 21 wk of gestation. Our results indicate that functional fetal γδ 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.

Defining the nature of human γδ T cells: a biographical sketch of the highly empathetic

“…90,91 It is therefore feasible that this change in cd T cell distribution observed in never-infected individuals from this West African population stems from evolutionary selection based on an immune advantage by those having a high proportion of Vd1 T cells-which would again align with the association of there being some adaptive influence of microbial exposure on the make-up of cd T cells in an organism. Other infectious diseases that are associated with the recruitment and expansion of specifically the Vd1 T cell subset in the periphery are cytomegalovirus, 33,92 Epstein-Barr virus 93,94 and HIV. 95,96 In most of these cases, the specific activation and expansion appears to be driven by the presentation of endogenous molecules rather than virally derived antigens-keeping with the notion that these T cells are particularly well adapted to sensing the turmoil within rather than relying exclusively on external validation.…”

Easier Control of Late-Onset Cytomegalovirus Disease Following Universal Prophylaxis Through an Early Antiviral Immune Response in Donor-Positive, Recipient-Negative Kidney Transplants

“…In this context, we and others have shown that Vd2-negative (Vd2 neg ) cd T cells are key effector components in the control of CMV infection (14)(15)(16). This subset, which is typically located within the epithelia, is characterized by the use of Vd1, Vd3 or Vd5 segments (collectively called Vd2 neg cd T cells), whereas the most common subset in the peripheral blood uses the association of Vd2 and Vc9 variable regions (Vc9/Vd2 T cells).…”

Cord blood Streptococcus pneumoniae-specific cellular immune responses predict early pneumococcal carriage in high-risk infants in Papua New Guinea

“…Accordingly, in‐utero infection with cytomegalovirus (CMV) has been found to result in in‐utero activation of fetal CMV T cell responses that, compared to adult responses, are ‘functionally exhausted’, with a limited capacity to control CMV replication 50, 51. Although pneumococcal‐specific cord blood cellular cytokine responses were lower overall in infants born to mothers who were pneumococcal carriers at the time of delivery, we were not able to find significant differences compared with responses of infants born to mothers who were non‐carriers: we believe that a more extensive upper respiratory tract pneumococcal carriage study during pregnancy would be needed, including a larger population size to estimate more clearly the effect of maternal carriage on immune priming.…”