The effect of inherited maternal cells on BCG-specific T cell responses in HIV exposed and unexposed infants - SUMMARY Each year, nearly 1.3 million exposed but uninfected infants (iHEU) are born. Compared to infants who were unexposed to HIV in utero (iHU), iHEU experience greater morbidity and mortality associated with infectious diseases, including Mycobacterium tuberculosis (Mtb) infection. To prevent disseminated Mtb in childhood, most infants born in Mtb-endemic settings receive bacille Calmette-Guerin (BCG) vaccine early in life. CD4+ T cell responses, particularly from the Th1 subset, are critical for controlling tuberculosis and are therefore used as a proxy for BCG vaccine immunogenicity. However, altered CD4+ T cell recall responses to BCG have been observed in iHEU, suggesting that the benefits of BCG may be reduced in these infants. As such, a more complete understanding of the factors influencing CD4+ T cell recall responses to BCG are critical to improve tuberculosis vaccination strategies in infants living in settings with high Mtb and HIV prevalence. Maternal microchimerism (MMc) at birth refers to the transmission of maternal cells to the offspring in utero, and we recently found in a cohort of South African infants that birth MMc strongly predicted BCG-specific recall CD4+ T cell responses during infancy. However, iHEU, and in particular those born to mothers who initiated antiretroviral therapy (ART) during pregnancy (“late ART”), had lower MMc at birth. Based on our preliminary data, we hypothesize that the reduced transmission of MMc in utero may function as an unrecognized mechanism of altered BCG-specific responses in iHEU. Work in animals indicates that the impact of MMc on offspring immunity may be mediated via either antigen-specific or antigen-independent effects. Based on these observations, we hypothesize that birth MMc is associated with improved infant BCG-specific CD4+ T cell recall responses through two potentially complementary mechanisms: i) by inducing mycobacterium-specific accentuation of the primary infant T cell responses to BCG and/or ii) by bolstering trained innate immunity in the infant leading to improved T cell responses. We further hypothesize that these mechanisms are restricted in iHEU versus iHU and particularly diminished within iHEU whose mothers initiated ART during versus prior to the pregnancy. To test these hypotheses, we will investigate the impact of MMc on infant CD4+ T cell BCG-specific responses using previously collected samples and data from iHEU and iHU enrolled in the InFANT cohort in South Africa. We will first determine the impact of maternal HIV exposure and ART timing on the in utero transmission of mycobacterium-specific T cells and polyfunctional T cell BCG recall response. We will next assess the relationship between birth MMc, trained immunity, and BCG-specific T cell recall response in iHEU and iHU. These studies will utilize previously collected samples and data from the InFANT cohort to elucidate the mechanisms underlying the association between MMc and improved BCG vaccine responses in iHEU and iHU, empowering future strategies to maximize protection against tuberculosis.
