The role of γδ T cells in fetal and infant immune defense against malaria

University Of California, San Francisco, San Francisco CA

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Abstract

T cells expressing the ?? TCR are the first to develop during human gestation and possess many features that make them uniquely suited to protection of the fetus and infant. Unlike conventional ?? T cells, ?? T cells recognize non-peptide antigens and can exhibit rapid, innate-like effector functions that are not dependent on prior antigen exposure nor on priming by dendritic cells, which are functionally immature in early life. A subset of ?? T cells (V?9V?2) respond to phosphoantigens produced by Plasmodium falciparum via a unique mode of presentation by ubiquitously expressed butyrophilin molecules. V?9V?2 T cells inhibit parasite replication in vitro and are associated with protection from P. falciparum parasitemia in vivo. Remarkably, V?9V?2 T cells that express a phosphoantigen-reactive ?? TCR and pre-programmed effector functions are already present in fetal blood at mid-gestation. These fetal V?9V?2 T cells have high inflammatory potential and can be rapidly activated to produce IFN? and granzymes upon stimulation. In addition, they express semi-invariant TCRs with distinct sequence characteristics, including limited junctional diversity and differential gene segment usage, that distinguish them from V?9V?2 T cells generated later in life. Given the intrinsic reactivity of V?9V?2 T cells to P. falciparum, we hypothesize that these cells may play a beneficial role as ready-made effectors during acute malaria infection of infants and young children, before an adaptive immune response has developed. We will use longitudinal samples previously collected from a large cohort of Ugandan infants, including cord blood mononuclear cells and infant PBMCs, to determine how V?9V?2 T cells respond to malaria antigen exposure in utero and during early childhood. In the first aim, we will characterize the expansion, differentiation, effector functions, and proliferative capacity of ?? T cells in infants following prenatal and postnatal malaria, enabling us to assess whether the V?9V?2 T cell response differs based on the timing of initial malaria exposure. In the second aim, we will evaluate the impact of malaria antigen exposure in utero and during early life on the ?? TCR sequence repertoire. This aim will incorporate single-cell sequencing technologies that pair transcriptomic information with TCR sequence data from individual cells, enabling us to resolve many potential sources of phenotypic and functional heterogeneity observed at the bulk cell analysis level. Lastly, V?9V?2 T cells have been shown to display APC-like capabilities including phagocytosis, antigen presentation, and even priming of naive T cells. Such functions may be of particular relevance during infancy, when professional APCs are immature and present antigen poorly. Therefore, in the third aim, we will investigate whether V?9V?2 T cells play additional roles in the fetus and neonate, beyond their immediate effector functions, including uptake and presentation of antigens to conventional ?? T cells and FcR-mediated recognition of opsonized antigens. Together, these experiments will illuminate the functional capabilities of a unique semi-innate effector T cell population and its role in protection against malaria during early life.