T cells play a critical role in eliminating pathogens and the generation of memory T cells is an important component in protection from secondary infection. Memory T cells can be broadly divided into two groups based on their location, those that are capable of circulating throughout the body and those that are lodged in tissues, poised to respond rapidly to secondary infection. Tissue-resident memory T cells (Trm) cells remain in the tissue and are not replenished by circulating cells after infection is resolved. Circulating T cells are often not sufficient to protect from secondary infection; therefore, it is of significant interest to determine how to maximize the number and functionality of Trm cells as they are critical for robust tissue-specific immunity. Only a small number of microbes need to breach the mucosal surface to initiate disease; however, the mechanism by which established Trm populations detect and migrate to new areas of infection remains unexplored. Our earlier work, using the intestinal bacterial pathogen Yersinia pseudotuberculosis (Yptb), identified two distinct CD8+ Trm populations in the intestine that are differentiated by their expression of the integrin CD103. CD103neg Trm cells preferentially localize to lymphocyte clusters that form around areas of infection and limit pathogen replication, but dissipate after infection is resolved. CD103neg CD4+ and CD8+ Trm populations are also abundant in other tissues, but their respective roles in tissue-specific immunity remain poorly understood. We hypothesize the diversity in the tissue-resident lymphocyte population underlies a functional heterogeneity, with the CD103neg subset of lymphocytes capable of localized migration in response to tissue-specific signals that alert them to a pathogenic insult and forms the basis for lymphocyte cluster formation around new areas of infection during secondary challenge. These studies will utilize photoconversion to mark tissue-resident cells and allowing us to track cellular migration during homeostasis and intestinal infection. We will leverage this technique to address fundamental gaps in our knowledge of Trm biology including: (1) how Trm diversity relates to functional outcomes during secondary infection and (2) the identification of signals generated by the tissue in response to infection that drive Trm mobilization and pathogen control. These experiments have the potential to significantly advance our understanding of tissue-resident lymphocyte biology and how immunization strategies can be tailored to improve Trm functionality.
|Effective start/end date||5/25/20 → 4/30/21|
- National Institute of Allergy and Infectious Diseases: $229,158.00