Mechanisms governing the priming and sustenance of encephalitogenic lymphocyte - stromal cell interactions during neurotropic viral infection

B cells are a key pathogenic mediator of CNS autoimmune disease, but also play a protective role in immune surveillance against latent neurotropic viral infections. Both pathological and immune surveillance properties of antibody-secreting cells require T cell-dependent priming in lymphoid organs and recruitment and retention in the CNS. Recent studies demonstrate that stromal cells steer efficient T and B cell interactions and effector functions in lymphoid organs. The spectrum of stromal cell-derived, immune-interacting niche factors is starting to be divulged based on known lymphocyte chemokine receptors. However, emerging transcriptomic studies reveal a potential wider array of stromal cell-expressed niche factors and maturation cues hinting towards a bi-directional crosstalk between lymphocytes and stromal cells in specifying dedicated immune cell interaction environments. Deciphering these molecular circuits is not only important for understanding how stromal - immune cell interactions orchestrate efficient lymphocyte priming, but may also reveal important mediators of inflammation-induced stromal cell niches that accompany chronic diseases, including those affecting the CNS. Indeed, immune-interacting stromal cells underpinning B cell-rich infiltrates are induced during autoimmune and antiviral neuroinflammation, suggesting that these cells may also orchestrate T-B cell interactions outside of lymphoid organs.In this project, we will address how stromal cells orchestrate efficient T-B cell interactions that lead to the encephalitogenic priming and sustenance of effector lymphocytes in the CNS during latent, neurotropic murine coronavirus (M-CoV) infection. In the first part of this project, we will employ specialized genetic models and high-resolution transcriptomics to systematically profile T and B cells responding to neurotropic M-CoV infection. In a second part, we will generate stromal cell-targeted genetic models and employ single cell and spatial transcriptomic technologies to identify novel mechanisms by which immune-interacting stromal cells steer the productive interaction and function of B and T cells in lymphoid tissues and in the CNS. Collectively, this project will reveal novel mechanisms governing the priming and sustenance of encephalitogenic B cells during neuroinflammatory disease. Identifying the cellular - molecular basis of stromal cell remodelling and lymphocyte retention is an area of intensive research for developing therapeutic strategies to dissolve these disease-propagating niches in chronic inflammatory diseases, including CNS autoimmune disease. The experimental results will reveal key molecular pathways steering the localized and timely interactions between lymphocytes and stromal cells, contributing to the intensive ongoing research to identify stromal cell-directed therapies to modulate chronic inflammatory disease.