programming of CCR10+ skin-homing innate lymphocytes in fetal thymus and adult skin-draining lymph nodes for establishment of skin immune system

Open Access
Author:
Yang, Jie
Graduate Program:
Molecular, Cellular and Integrative Biosciences
Degree:
Doctor of Philosophy
Document Type:
Dissertation
Date of Defense:
June 12, 2015
Committee Members:
  • Na Xiong, Dissertation Advisor
  • Margherita Teresa Anna Cantorna, Committee Member
  • Pamela Hankey Giblin, Committee Member
  • Girish Soorappa Kirimanjeswara, Committee Member
  • Yanming Wang, Committee Member
Keywords:
  • innate lymphoid cells
  • skin-homing
  • CCR10
  • fetal thymic programming
Abstract:
The skin is directly exposed to the environment and immune cells in the skin provide the first line of protection against invading pathogens. Innate and innate-like lymphocytes respond quickly during infection and coordinate with adaptive immune system to clear pathogens. Innate lymphoid cells (ILCs) are innate lymphocytes that lack rearranged antigen-specific receptors and preferentially localized in barrier tissues, such as skin. They play critical roles in homeostatic regulation but also contribute to inflammatory diseases when dysregulated. Mechanisms regulating the development and function of ILCs in the skin are poorly understood. I report that during the perinatal stage, the skin-specific homing property and effector potential of thymic natural killer (NK) cells, a subset of ILCs, are programmed in the thymus for their rapid localization into the skin and functions. This may represent an evolutionally important mechanism that directs innate lymphocytes to the skin of newborns, whose adaptive immune system has not fully developed, for early protection. Moreover, NK cells, including thymic NK cells, generated in the perinatal stage contribute to the skin immune system in adults. In addition, skin-homing ILCs can be generated in skin-draining lymph nodes (sLNs) of adults. Under homeostatic condition, ILCs are continuously activated in sLNs to acquire the expression of CCR10 for their localization into the skin. Foxn1 and Notch/ligands signals are involved in the induction of CCR10 expression on ILCs in fetal/neonatal thymi and adult sLNs for their skin localization. The generation of CCR10+ ILCs and their maintenance in the skin are dependent on T cell-regulated homeostatic environments and are suppressed under inflammatory conditions. Reciprocally, ILCs regulate the homeostasis of skin-resident T cells. My findings provide insights of mechanisms that regulate the establishment of innate lymphocytes in the skin and their cross-regulation with adaptive immune cells.