Brain resident memory T cells rapidly expand and initiate neuroinflammatory responses following CNS viral infection.

The contribution of circulating verses tissue resident memory T cells (TRMs) to clinical neuropathology is an enduring question due to a lack of mechanistic insights. The prevailing view is TRMs are protective against pathogens in the brain. However, the extent to which antigen-specific TRMs induce neuropathology upon reactivation is understudied. Using the described phenotype of TRMs, we found that brains of naïve mice harbor populations of CD69+ CD103- T cells. Notably, numbers of CD69+ CD103- TRMs rapidly increase following neurological insults of various origins. This TRM expansion precedes infiltration of virus antigen-specific CD8 T cells and is due to proliferation of T cells within the brain. We next evaluated the capacity of antigen-specific TRMs in the brain to induce significant neuroinflammation post virus clearance, including infiltration of inflammatory myeloid cells, activation of T cells in the brain, microglial activation, and significant blood brain barrier disruption. These neuroinflammatory events were induced by TRMs, as depletion of peripheral T cells or blocking T cell trafficking using FTY720 did not change the neuroinflammatory course. Depletion of all CD8 T cells, however, completely abrogated the neuroinflammatory response. Reactivation of antigen-specific TRMs in the brain also induced profound lymphopenia within the blood compartment. We have therefore determined that antigen-specific TRMs can induce significant neuroinflammation, neuropathology, and peripheral immunosuppression. The use of cognate antigen to reactivate CD8 TRMs enables us to isolate the neuropathologic effects induced by this cell type independently of other branches of immunological memory, differentiating this work from studies employing whole pathogen re-challenge. This study also demonstrates the capacity for CD8 TRMs to contribute to pathology associated with neurodegenerative disorders and long-term complications associated with viral infections. Understanding functions of brain TRMs is crucial in investigating their role in neurodegenerative disorders including MS, CNS cancers, and long-term complications associated with viral infections including COVID-19.

Sign Tracking, but Not Goal Tracking, is Resistant to Outcome Devaluation.

During Pavlovian conditioning, a conditioned stimulus (CS) may act as a predictor of a reward to be delivered in another location. Individuals vary widely in their propensity to engage with the CS (sign tracking) or with the site of eventual reward (goal tracking). It is often assumed that sign tracking involves the association of the CS with the motivational value of the reward, resulting in the CS acquiring incentive value independent of the outcome. However, experimental evidence for this assumption is lacking. In order to test the hypothesis that sign tracking behavior does not rely on a neural representation of the outcome, we employed a reward devaluation procedure. We trained rats on a classic Pavlovian paradigm in which a lever CS was paired with a sucrose reward, then devalued the reward by pairing sucrose with illness in the absence of the CS. We found that sign tracking behavior was enhanced, rather than diminished, following reward devaluation; thus, sign tracking is clearly independent of a representation of the outcome. In contrast, goal tracking behavior was decreased by reward devaluation. Furthermore, when we divided rats into those with high propensity to engage with the lever (sign trackers) and low propensity to engage with the lever (goal trackers), we found that nearly all of the effects of devaluation could be attributed to the goal trackers. These results show that sign tracking and goal tracking behavior may be the output of different associative structures in the brain, providing insight into the mechanisms by which reward-associated stimuli-such as drug cues-come to exert control over behavior in some individuals.