Kidney-infiltrating T cells in murine lupus nephritis are metabolically and functionally exhausted
Jeremy S. Tilstra, Lyndsay Avery, Ashley V. Menk, Rachael A. Gordon, Shuchi Smita, Lawrence P. Kane, Maria Chikina, Greg M. Delgoffe, Mark J. Shlomchik
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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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 5

The transcriptional profile of KITs is consistent with T cell exhaustion.

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The transcriptional profile of KITs is consistent with T cell exhaustion...
(A and B) RNA-seq data were used to construct gene set enrichment plots illustrating genes differentially regulated in kidney- compared with splenic-derived T cells (n = 3 per group) with respect to a known set of 194 CD4+ expressed and 200 CD8+ expressed genes specific for LCMV-induced T cell exhaustion (44) in both the CD8+ (A) and CD4+ (B) compartments. MitoStatus values calculated using the conservative rankSumTestWithCorrelation function in the limma package. (C) Unbiased hierarchical clustering was performed using 1,426 genes previously identified from 10 clusters comparing TILs to activated and naive T cell populations (36) and represented as a heatmap. Row annotation on the heatmap shows association of clustered genes with PD-1+Tim3+ TILs (purple), naive, effector, and PD-1– Tim3– TILs (gray) or those with enhanced gene expression in both subgroups (orange) (36). GSEA was also performed on individual clusters (Supplemental Figure 6). (D) Differential expression between kidney and splenic CD8+ T cells for selected IRs, T cell products, and metabolic genes as determined by RNA-seq. (E) Representative contour plots for Tcf1 and Eomes expression in nonexhausted (black), exhausted (PD-1+ Tim3+ T cells from LCMV-infected mice) (green), or MRL/lpr kidney- (red) or splenic-derived (blue) CD8+ T cells. For tabulated data, each dot denotes an individual mouse, and bars represent the mean, with error bars indicating SD. One-way ANOVA was used to determine statistical significance using Tukey’s test for multiple comparisons. **P < 0.01; ****P < 0.0001.