Tissue-resident memory T cells break tolerance to renal autoantigens and orchestrate immune-mediated nephritis.

Immune-mediated nephritis is a leading cause of acute kidney injury and chronic kidney disease. While the role of B cells and antibodies has been extensively investigated in the past, the advent of immune-checkpoint inhibitors has led to a reappraisal of the role of T cells in renal immunology. However, it remains elusive how T cells with specificity for renal autoantigens are activated and participate in immune-mediated nephritis. Here, we followed the fate and function of pathogen-activated autoreactive CD8 T cells that are specific for a renal autoantigen. We demonstrate that recently activated splenic CD8 T cells developed a hybrid phenotype in the context of renal autoantigen cross-presentation, combining hallmarks of activation and T cell dysfunction. While circulating memory T cells rapidly disappeared, tissue-resident memory T cells emerged and persisted within the kidney, orchestrating immune-mediated nephritis. Notably, T cells infiltrating kidneys of patients with interstitial nephritis also expressed key markers of tissue residency. This study unveils how a tissue-specific immune response can dissociate from its systemic counterpart driving a compartmentalized immune response in the kidneys of mice and man. Consequently, targeting tissue-resident memory T cells emerges as a promising strategy to control immune-mediated kidney disease.

α-Parvin Defines a Specific Integrin Adhesome to Maintain the Glomerular Filtration Barrier.

BACKGROUND: The cell-matrix adhesion between podocytes and the glomerular basement membrane is essential for the integrity of the kidney's filtration barrier. Despite increasing knowledge about the complexity of integrin adhesion complexes, an understanding of the regulation of these protein complexes in glomerular disease remains elusive. METHODS: We mapped the in vivo composition of the podocyte integrin adhesome. In addition, we analyzed conditional knockout mice targeting a gene (Parva) that encodes an actin-binding protein (α-parvin), and murine disease models. To evaluate podocytes in vivo, we used super-resolution microscopy, electron microscopy, multiplex immunofluorescence microscopy, and RNA sequencing. We performed functional analysis of CRISPR/Cas9-generated PARVA single knockout podocytes and PARVA and PARVB double knockout podocytes in three- and two-dimensional cultures using specific extracellular matrix ligands and micropatterns. RESULTS: We found that PARVA is essential to prevent podocyte foot process effacement, detachment from the glomerular basement membrane, and the development of FSGS. Through the use of in vitro and in vivo models, we identified an inherent PARVB-dependent compensatory module at podocyte integrin adhesion complexes, sustaining efficient mechanical linkage at the filtration barrier. Sequential genetic deletion of PARVA and PARVB induces a switch in structure and composition of integrin adhesion complexes. This redistribution of these complexes translates into a loss of the ventral actin cytoskeleton, decreased adhesion capacity, impaired mechanical resistance, and dysfunctional extracellular matrix assembly. CONCLUSIONS: The findings reveal adaptive mechanisms of podocyte integrin adhesion complexes, providing a conceptual framework for therapeutic strategies to prevent podocyte detachment in glomerular disease.