EXPANSION OF BRAIN T CELL SUBSETS OUTSIDE OF THE CHOROID PLEXUS IN MOUSE MODELS OF NEUROPSYCHIATRIC LUPUS

O046 / #556 Topic:AS02 - Animal Models ABSTRACT CONCURRENT SESSION 07: COGNITION IMPAIRMENT IN SLE — RECENT ADVANCEMENT AND EMERGING RESEARCH 23-05-2025 1:40 PM - 2:40 PM Background/Purpose Unclear mechanisms underlying diffuse NPSLE (psychosis, anxiety disorder, cognitive dysfunction) may lead to the devastating impact of this disease on patients’ health-related quality of life, representing a major unmet need in the field. In prior work, systemic depletion of CD4+ T cells ameliorated both systemic disease and behavior deficits in SLE- and NPSLE-prone MRL/lpr mice by reducing choroid plexus-infiltrating CD4+ T cells as well as indirectly preventing CD8+ T cell infiltration. Further, increased markers of exhaustion were identified in choroid plexus-infiltrating CD8+ T cells of MRL/lpr mice. However, NPSLE is heterogeneous in its presentation; choroid plexus infiltrate is not a fully penetrant hallmark of human NPSLE or other disease models. Thus, it is critical to elucidate the contribution of T cell subsets outside of the choroid plexus to NPSLE. Methods Perfused brains of female SLE- and NPSLE-prone CReCOM (8 mo old; n=4-11) and B6.Sle1Sle2Sle3(TC; 2 and 8 mo old; n=3-4) mice, and respective control strains, were extracted after intravenous CD45 labeling to exclude remaining circulating immune cells, dural meninges were removed, and cells were analyzed by flow cytometry. Young female CD45.1 (Jackson 033076) and TC mice were used to generate reciprocal head-shielded BM chimeric mice with busulfan treatment to clear remaining BM (CD45.1 BM::CD45.1; TC BM::CD45.1; CD45.1 BM::TC; TC BM::TC). Mice underwent behavioral tasks 10 weeks post-transfer. Live CD45+cells were FACSorted from pooled cell suspensions (n=3/group to account for biological variability) for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq; 10X Genomics 3’ v3.1). Data from CD45.1 BM::CD45.1 and TC BM::TC chimeras were analyzed in R using the Seurat package. Post-filtering, ~10K cells/chimera were maintained. Results Extravascular CD8+ T cells are significantly increased in the brains of CReCOM and TC mice (8 mo old) compared to their respective control strains. Further, this increase is evident at 2 months of age in TC mice. Evaluation of extravascular T cells by CITE-seq in CD45.1 BM::CD45.1 and TC BM::TC chimeric mice was carried out to mimic that of control and NPSLE-prone strains, respectively, in systemic disease and behavioral phenotypes. Similar to data from the kidney and choroid plexus of MRL/lpr mice, we show expansion of an exhausted (Pdcd1, Eomes, Tox) CD8+ T cell subset. We also identify an expanded IL-17-producing gamma-delta T cell subset previously unassociated with NPSLE-like disease but implicated in neuro-autoimmune and -degenerative diseases (multiple sclerosis, Alzheimer’s disease). As CReCOM and TC mice do not present with the characteristic choroid plexus infiltrate of the MRL/lpr strain, these subsets mediate their activity in the brain parenchyma or nondural meninges. Conclusions We find expansion of an exhausted CD8+ T cell subset in the brain of NPSLE-prone mice that may transition from a highly activated T cell state. An IL-17-producing gamma-delta T cell subset not previously associated with NPSLE was also expanded. Future studies will interrogate these specialized T cell subsets for their location of action to further uncover their role of in NPSLE-like disease.

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