Date of Award

2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Microbiology and Immunology

Abstract

The perinatal immune system is highly tolerogenic and is phenotypically and functionally distinct from the adult immune system. This tolerogenic nature is a double-edged sword for newborns. While it is beneficial to prevent excessive inflammation against the vast array of foreign antigens encountered after birth, it also causes a lack of immune responses to life-threatening infections. My dissertation research aims to investigate the mechanisms by which perinatal T cells contribute to immune tolerance in infants. A deeper understanding of the nature of the perinatal immune system will provide pivotal knowledge to develop safe and effective strategies to protect infants from infection and to establish immune homeostasis with commensal microbes. Using umbilical cord blood (UCB) T cells as a model to study perinatal immunity, we found that antigen receptor stimulation of T cells in UCB leads to the development of Foxp3+ T cells in both CD4+ and CD8+ T cell subsets. These UCB-derived Foxp3+ T cells are phenotypically and epigenetically distinct from canonical thymus-derived Tregs (tTregs) in adults, but they carry immune regulatory functions in vitro and in vivo. The development of Foxp3+ T cells requires CD36hi monocytes. Adult blood contains a group of lymphocytes that inhibits monocyte-induced Foxp3+ T cell development, showing how perinatal blood differs from adult blood. Foxp3+ T cell development also requires IL-2. Alcohol, which is known to cause immunological defects, reduces the expression of CD25, a component of the high affinity IL-2 receptor, and blocks Foxp3+ T cell development. The result suggests that immunological dysfunctions found among infants born from alcoholic mothers may be in part due to the impaired development of these Foxp3+ T cells during their fetal life. To further elucidate the mechanisms that contribute to perinatal immunological tolerance, we investigated the expression of Helios, another transcription factor known to be expressed by tTregs along with Foxp3. We found that Helios is expressed significantly more frequently by UCB and neonatal peripheral blood T cells than adult T cells. Similar results were observed in mice. The expression frequency decreased rapidly after birth. The data suggested that T cells from fetal/perinatal origin express Helios. Indeed, we found that most gut-associated T cells, which are known to originate from the fetal thymus, express Helios in the fetus and maintained Helios expression throughout adulthood. Additionally, human T cells that matured in mice that received UCB hematopoietic stem cells also express Helios. Gene knockout of Helios in UCB T cells showed a significant increase in expression of multiple effector cytokines, suggesting that one of Helios' functions is to suppress effector cytokine production by activated T cells. Together, these data demonstrated multiple mechanisms by which T cells can contribute to immune tolerance in neonates. First, the perinatal peripheral environment promotes T cells to differentiate into a unique group of Foxp3+ T cells that carry suppressive functions. Second, perinatal T cells express high levels of Helios, which suppress activated T cells to produce effector cytokines. Together, both intrinsic (Helios) and extrinsic (CD36hi monocytes) mechanisms promote the tolerogenic nature of the perinatal immune system.

Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.

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