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Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted
Jeremy S. Tilstra, … , Greg M. Delgoffe, Mark J. Shlomchik
Jeremy S. Tilstra, … , Greg M. Delgoffe, Mark J. Shlomchik
Published August 21, 2018
Citation Information: J Clin Invest. 2018;128(11):4884-4897. https://doi.org/10.1172/JCI120859.
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Research Article Autoimmunity Immunology

Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted

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Abstract

While T cells are important for the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis, little is known about how T cells function after infiltrating the kidney. The current paradigm suggests that kidney-infiltrating T cells (KITs) are activated effector cells contributing to tissue damage and ultimately organ failure. Herein, we demonstrate that the majority of CD4+ and CD8+ KITs in 3 murine lupus models are not effector cells, as hypothesized, but rather express multiple inhibitory receptors and are highly dysfunctional, with reduced cytokine production and proliferative capacity. In other systems, this hypofunctional profile is linked directly to metabolic and specifically mitochondrial dysfunction, which we also observed in KITs. The T cell phenotype was driven by the expression of an “exhausted” transcriptional signature. Our data thus reveal that the tissue parenchyma has the capability of suppressing T cell responses and limiting damage to self. These findings suggest avenues for the treatment of autoimmunity based on selectively exploiting the exhausted phenotype of tissue-infiltrating T cells.

Authors

Jeremy S. Tilstra, Lyndsay Avery, Ashley V. Menk, Rachael A. Gordon, Shuchi Smita, Lawrence P. Kane, Maria Chikina, Greg M. Delgoffe, Mark J. Shlomchik

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Figure 6

Nephritic kidneys from MRL/lpr mice locally express PD-L1 near sites of T cell infiltration.

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Nephritic kidneys from MRL/lpr mice locally express PD-L1 near sites of ...
PD-L1 expression on kidneys of nephritic (>20 weeks) and prenephritic (4 weeks) MRL/lpr mice was assessed by immunofluorescence microscopy: CD4+ (green), CD8+ (white), and PD-L1 (red) expression. Merged and single-color images are shown for each stain. Scale bars: 50 μm (insets).

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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