Characterisation of choroid plexus-infiltrating T cells reveals novel therapeutic targets in murine neuropsychiatric lupus.

OBJECTIVE: Diffuse central nervous system manifestations, referred to as neuropsychiatric lupus (NPSLE), are observed in 20-40% of lupus patients and involve complex mechanisms that have not yet been adequately elucidated. In murine NPSLE models, choroid plexus (ChP)-infiltrating T cells have not been fully evaluated as drivers of neuropsychiatric disease. METHOD: Droplet-based single-cell transcriptomic analysis (single-cell RNA sequencing) and immune T-cell receptor profiling were performed on ChP tissue from MRL/lpr mice, an NPSLE mouse model, at an 'early' and 'late' disease state, to investigate the infiltrating immune cells that accumulate with NPSLE disease progression. RESULTS: We found 19 unique clusters of stromal and infiltrating cells present in the ChP of NPSLE mice. Higher resolution of the T-cell clusters uncovered multiple T-cell subsets, with increased exhaustion and hypoxia expression profiles. Clonal analysis revealed that the clonal CD8+T cell CDR3 sequence, ASGDALGGYEQY, matched that of a published T-cell receptor sequence with specificity for myelin basic protein. Stromal fibroblasts are likely drivers of T-cell recruitment by upregulating the VCAM signalling pathway. Systemic blockade of VLA-4, the cognate ligand of VCAM, resulted in significant resolution of the ChP immune cell infiltration and attenuation of the depressive phenotype. CONCLUSION: Our analysis details the dynamic transcriptomic changes associated with murine NPSLE disease progression, and highlights its potential use in identifying prospective lupus brain therapeutic targets.

Mechanisms of self-inactivation in anergic T cells

Las células T autorreactivas que escapan al proceso de selección negativa en el timo han de ser inactivadas o eliminadas en la periferia. En respuesta a una estimulación parcial o subóptima, las células T se vuelvenanérgicas e incapaces de proliferar y producir citocinas en respuesta aencuentros posteriores con el antígeno. Las señales mediadas por calcio tienen un papel importante en la inducción de anergia, por medio de la activación de un programa de auto-inactivación intrínseco a la célula dependiente de calcio/calcineurina/NFAT. Esta revisión se centra en la descripción de nuestros conocimientos actuales acerca de los mecanismos reguladores de la expresión de un programa de expresión génica específico dela anergia de las células T, y cómo las proteínas codificadas por esos genesimponen un estado funcional falta de respuesta a nuevos estimulos. Estose lleva a cabo mediante la localización y la modulación de la actividadde sucesos cruciales para la activación de las células T, incluyendo fenó-menos como la atenuación de las señales del receptor de linfocitos T (TCR)y la inhibición de la transcripción de citocinas (AU)

Self-reactive T cells that escape negative selection in the thymus mustbe inactivated or eliminated in the periphery. In response to a partial orsuboptimal stimulation, T cells become anergic and unable to proliferate and express cytokines in response subsequent re-encounters with antigen. Calcium signaling plays a central role in the induction of anergy, causing the activation of a calcium/calcineurin/NFAT-dependent cell-intrinsic program of self-inactivation. This review will focus on our currentknowledge on the mechanisms that regulate the expression of an anergyspecific program of gene expression in T cells, and how the proteins encoded by those genes impose a state of functional unresponsiveness by targeting and modulating the activity of crucial events required for the activation of T cells, which include downregulation of TCR signaling andinhibition of cytokine transcription (AU)