Dissecting the Neonatal CD4+ T cell Response to Mycobacterium tuberculosis

152 pagesNeonates are highly susceptible to morbidity and mortality from infectious disease. Neonates are particularly vulnerable to Mycobacterium tuberculosis (Mtb) infection, and develop a more fatal form of Tuberculosis (TB). CD4+ T cells are essential to the adaptive immune response to Mtb, and have been long thought to be impaired in early life at responding to infection. Therefore, neonatal CD4+ T cells may contribute to the more severe TB disease phenotype seen in neonates, and understanding the behavior of neonatal CD4+ T cells is key to preventing disease in this vulnerable population. While previous work has indicated that neonatal CD4+ T cells preferentially adopt a Th2 and T regulatory (Treg) fate, an unknown has been how neonatal CD4+ T cells are capable of responding to a variety of inflammatory conditions, and whether these properties are retained into adulthood by the neonatal layer of CD4+ T cells. We exposed neonatal CD4+ T cells to multiple T helper conditions in vitro, and found that while under neutral conditions they do retain a Th2 skew, they are equally as capable of responding to all tested conditions as adult CD4+ T cells. Next, we investigated whether the upregulation of the RNA binding protein, Lin28b, early in life in CD4+ T cells underlies the phenotype of neonatal CD4+ T cells, finding that Lin28b overexpression in adult CD4+ T cells does cause a Th2 skew. Finally, we examined whether these unique characteristics of neonatal CD4+ T cells are retained into adulthood using a fate mapping mouse model. Our studies indicated that neonatal CD4+ T cells do persist into adulthood and preferentially adopt a Treg fate. Using an alternate method, by thymectomizing young mice, we confirmed that adult mice with only a neonatal layer of CD4+ T cells also have increased percentages of Treg cells. Finally, in this thesis, we examined the role of neonatal CD4+ T cells in responding to Mtb. Our studies, utilizing an adoptive transfer experiment in which neonatal and adult CD4+ T cells specific to an Mtb antigen were transferred into adult mice, indicated that neonatal CD4+ T cells can sufficiently respond to Mtb during early infection. However, during chronic Mtb infection, neonatal CD4+ T cells become terminally differentiated and fail to localize properly to the site of infection in the lung parenchyma. Additionally, we found that when the neonatal layer of CD4+ T cells are depleted prior to infection, there is an earlier CD4+ T cell response and a modest decrease in Mtb burden late in infection. Finally, we developed a neonatal Mtb infection model, which indicated that the inflammatory response is histologically less organized and effective in containing Mtb in chronic infection. Collectively, this thesis highlights the various roles of neonatal CD4+ T cells through adulthood, and indicates that the developmental origin of CD4+ T cells may play a role in the response to Mtb.2024-09-0