Tissue-resident immune cell populations have extensive effects on the function of nonlymphoid tissues in homeostasis and inflammation. Many of these immune cells first migrate to tissues during highly specific periods of postnatal development when their host organs are still maturing. Understanding how immune cells influence tissues during this critical developmental period is likely to be relevant to the pathogenesis of autoimmune and allergic disease, many of which originate in barrier tissues at this time. However, specific cellular mechanisms by which immune cells interact with parenchymal and stromal cells during postnatal development remain elusive. Regulatory T cells (Tregs) are critical suppressors of inflammation and autoimmunity that establish residence in many organs including neonatal skin. Preliminary data presented herein show that neonatal Tregs enforce normal development of the skin stroma by suppressing the outgrowth of a fibrosis-like stromal population. Single cell RNA sequencing revealed novel skin stromal populations that express receptors for T cell-derived cytokines, are enriched for expression of inflammatory cytokines, and are inhibited by neonatal Tregs. Transient loss of neonatal Tregs also leads to the accumulation of skin-resident Th2 cells. This proposal will test the hypothesis that dysfunctional stromal development, normally held in check by Tregs, can create niches for pathogenic Th2 cells that increase the susceptibility to future inflammation in adulthood. First, the response of these novel skin stromal celltypes to inflammatory cues will be mechanistically defined (Aim 1). Stromal-specific cytokine deletion will then be used to test how the stroma affects the accumulation of skin Th2 cells (Aim 2). Lastly, this proposal will test whether transient loss of neonatal Tregs increases the susceptibility to future skin inflammation (Aim 3). Data from these aims will elucidate key mechanisms by which the immune system influences tissue development and regulates inflammation in the postnatal period, which may yield valuable insights into the mechanisms of early life sensitization to human immunological diseases. These research goals will be conducted in conjunction with a comprehensive training plan to develop the applicant?s career as a physician-scientist. Training includes structured, rigorous mentorship in scientific and technical skills from a highly qualified physician-scientist sponsor, carried out through regular individual and group meetings, classes, seminars, journal clubs, and departmental events. Research and training will take place at the University of California, San Francisco, which offers both an outstanding immunology research environment and an excellent medical school for clinical training.
Although infancy and childhood are known to be a critical period for immunological development, specific mechanisms that account for the onset of many autoimmune and allergic diseases at this time are unknown. We have found that skin-resident regulatory T cells (Tregs) generated during this developmental window are critical both for regulating the development of the skin stroma and preventing the accumulation of Th2 cells in the skin. This proposal will build off these preliminary data to mechanistically dissect how transient deficiencies in early-life immune tolerance may establish susceptibility to disease in adulthood by causing dysfunctional tissue development.
