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Immune ontogeny and lymphocyte responses to primary herpesvirus infections in Ugandan infants Tuengel, Jessica


Herpesviruses cytomegalovirus (CMV) and Epstein-Barr virus (EBV) cause an enormous burden of disease worldwide. Congenital CMV (cCMV) is the most common congenital infection in the world and can cause deafness and intellectual disability. EBV is the causal agent of Burkitt’s lymphoma (most common pediatric cancer in Africa), infectious mononucleosis, and associated with several autoimmune diseases. Age-related differences in symptoms and diseases caused by all herpesviruses likely reflect immune variation early in life, however lymphocyte responses to EBV and CMV are not well documented in young children. Gamma delta (γδ) T cells develop early in gestation and may be important for controlling CMV infection before alpha beta T cell immunity develops. Indeed, a “public” (shared among many individuals) γδ T cell receptor (TCR) clone has been associated with cCMV and may represent an important early response to the virus. In this study we aimed to describe general immune ontogeny and lymphocyte responses to herpesvirus infections in infancy and comprehensively characterize γδ T cell responses to CMV infection in infants. Following a birth cohort of 32 Ugandan infants and their mothers during their first year of life, we captured 20 CMV and 10 EBV primary infections. Using standard flow cytometry, we characterized a wide range of innate and adaptive lymphocytes and further characterized the γδ T cells from a subset of the cohort with a 21-color spectral flow cytometry panel and extracted RNA for TCR sequencing. In the first year of life, there were significant ontological changes within all lymphocyte subsets tested (natural killer (NK) cells, B cells, T cells). NK and T cell compartments experienced the most dramatic changes with CMV infection. Age and CMV infection were correlated with γδ T cells and EBV was not. Unsupervised clustering analyses revealed CMV-specific adaptive-like γδ T cell subsets with effector phenotypes in infants and adults. Our findings provide evidence of the cell types involved in primary herpesvirus infections during infancy and support the notion that γδ T cells are participating in the immune response to CMV infection in early life, providing insight for novel new vaccine designs to more effectively prevent CMV-related disease.

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