Role of S1PRs and KLF transcription factors in CD8T cell trafficking

PROJECT ABSTRACT CD8+ T cells are pivotal players in the adaptive immune response, undergoing dynamic functional transitions crucial for mounting effective responses to antigens. Upon encountering pathogens, CD8+ T cells differentiate into effector cells responsible for pathogen clearance and memory T cells providing long-term protection against reinfections. Concurrently, migratory patterns of CD8+ T cells change with differentiation, where naïve T cells recirculate, effector and circulating memory T cells (TCIRCM) distribute into various tissues, and resident memory T cells (TRM) become localized long-term in tissues. Krüppel-like factor 2 (KLF2) emerges as a critical regulator of T cell trafficking, particularly through its control of Sphingosine-1-phosphate receptor 1 (S1PR1) expression. While expression of KLF2 or S1PR1 inhibits TRM formation, its role in regulating other aspects of T cell trafficking remains incompletely understood. Additionally, it is unclear whether KLF2 maintains memory T cell trafficking patterns beyond initial differentiation. This study aims to address these gaps by elucidating the mechanisms of S1PR1-independent KLF2-regulated CD8+ T cell trafficking and differentiation (Aim 1). Leveraging genetic manipulation and gene expression analysis, we will explore redundancy among S1PR factors and investigate non-S1PR molecules in effector and memory T cell trafficking. Furthermore, we will uncouple T cell trafficking from KLF2 expression to assess its influence on differentiation. In Aim 2, we will evaluate the role of KLF2 in reinforcing memory T cell recirculation versus tissue residency. Through inducible gene expression/deletion models, we will determine how KLF2 modulation affects TRM and TCIRCM migration characteristics post-establishment of memory. This investigation holds therapeutic implications for manipulating memory T cell localization, crucial in combating pathogens and tumors while resisting exhaustion. Overall, this comprehensive study will deepen our understanding of KLF2's multifaceted role in CD8+ T cell trafficking and function, offering insights into potential therapeutic strategies for immune modulation in various disease contexts.