Sounding the alarm: Local cues that drive functional specialization of brain resident memory T cells

Author

Shawn Christopher Musial Jr., Dartmouth CollegeFollow

Author ORCID Identifier

https://orcid.org/0000-0002-4146-1503

Date of Award

Summer 8-15-2024

Document Type

Thesis (Ph.D.)

Department or Program

Microbiology and Immunology

First Advisor

Pamela Rosato

Abstract

Resident memory T cells are a unique subset of memory T cells that persist within tissues throughout the body, including the brain, optimally positioned to exert local immune activation. Broadly, T cells in the CNS are implicated in a range of neurologic disorders, can protect against reinfection, and even participate in normal CNS homeostasis. Despite this, there remain significant gaps in knowledge about how T cells, specifically resident memory T cells (T_RM), are regulated and function in the unique CNS environment. Here, we leverage a mouse model of acute viral infection to dissect the diversity of brain T_RM (bT_RM) and their impact on local immune environment.

Our data confirmed previous findings that bT_RM express markers associated with T cell exhaustion, such as PD-1. Despite this inhibitory profile, we show that intracranial delivery of cognate viral peptide led to robust bT_RM reactivation and initiated a cascade of immune activation and accumulation within the brain, including rapid activation of microglia, NK cells and T cells, DC maturation, and infiltration of macrophages and monocyte derived DCs. In the presence of PD-L1 blockade or genetic deletion of PD-1, despite observing higher effector molecule production from reactivated bT_RM, we found no apparent difference in downstream immune activation in the brain nor enhanced bT_RM mediated protection from reinfection.

Through single cell RNA sequencing we find unique bT_RM populations with transcriptional signatures predictive of distinct functions. Interestingly, we find that the route of initial infection shapes population diversity of established bT_RM months after the infection has cleared. We describe a novel role for IFNb signaling and local antigen encounter in programming cytolytic bT_RM seeded through intranasal, but not intravenous infection. Additionally, we report shared subsets of bT_RM conserved between infection routes, indicative of a core bT_RM transcriptional profile.

Our studies demonstrate the capacity for T_RM alarm functions to potently activate local immunity and illuminate a previously unappreciated role for local antigen in shaping bT_RM heterogeneity, reflective of diverse functions. Collectively, these data provide a foundational knowledge base upon which to contextualize the role of T_RM in pathogenic settings and may guide therapies to target these cells.

Recommended Citation

Musial, Shawn Christopher Jr., "Sounding the alarm: Local cues that drive functional specialization of brain resident memory T cells" (2024). Dartmouth College Ph.D Dissertations. 288.
https://digitalcommons.dartmouth.edu/dissertations/288