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

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 4

KITs are metabolically suppressed.

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KITs are metabolically suppressed. (A) Representative oxygen consumption...
(A) Representative oxygen consumption rate (OCR) trace (left) from sorted CD4+ and CD8+ T cells isolated from kidney (red) and spleen (blue) of MRL/lpr mice. A metabolic stress test was performed by injection of oligomycin (Oligo), mitochondrial decoupler (FCCP), glucose uptake inhibitor (2-DG), and antimycin A/rotenone (Ant/Rot). SRC was calculated as the difference between basal OCR values and maximal OCR values achieved after FCCP uncoupling. Summary data of SRC ratio, defined as SRC divided by basal OCR, is shown on the right (n = 7 per group). Error bars at each time point in the trace represent mean ± SEM of triplicate wells, with tabulated data in dot plots (right panels). (B) The Δψm was assessed by flow cytometry using MitoStatus dye. Representative histograms (red, kidney; blue, spleen) of MitoStatus from T cell lineages as indicated from both MRL/lpr (upper left panel) and Fcgr2b–/–.Yaa mice (lower left panel), with tabulated data in dot plots (right panels) (n = 5 per group), are shown (C) Mitochondrial mass was assessed by flow cytometry using MitoTracker DR. Representative histograms (red, kidney; blue, spleen) of MitoTracker DR from T cell lineages as indicated from MRL/lpr mice with summary data in dot plots (lower panels) (n = 5 per group). (D) Representative contour plots of BALB/c splenic or MRL/lpr splenic- or kidney-derived CD4+ (top) and CD8+ (bottom) T cells showing 2NBDG (glucose uptake) and MitoStatus staining, with summary data in dot plots (BALB/c, n = 2; MRL/lpr n = 5 mice). For tabulated data (B–D), each dot denotes an individual mouse, and horizontal lines represent the mean, with error bars representing 1 SD. Paired Student’s t test was used to determine statistical significance between spleen and kidney samples. **P < 0.01; ***P < 0.001; ****P < 0.0001.