Fig. 5: The integrated stress response pathway is downregulated in T_RM cells in patients with inflammatory diseases.

a, UMAP plot showing the distribution of CD4⁺KLF2⁻CD69⁺ T_RM cells, CD4⁺SELL⁻ KLF2⁺CD69⁻ T_EM cells and CD4⁺SELL⁺KLF2⁺CD69⁻ T_CM/T_N cells isolated from the kidney of healthy controls (n = 3) and patients with ANCA-GN (n = 5) (left) and heatmap showing the expression of CD69, CCR7, CD62L and CD45RA protein and KLF2, S1PR1, CCR7, SELL, IFNG, TNF, IL17A, IL17F and CSF2 mRNA in the CD4⁺ T_RM, T_EM and T_CM/T_N cell clusters defined in the UMAP (right). b, Violin plot showing cytokine scores based on the expression of IL2, IL17A, IL17F, IL22, IFNG, TNF, CSF2 and LTA in kidney CD4⁺ T_RM cells from healthy controls and patients with ANCA-GN as in a. c, Reactome analysis showing downregulated pathways in kidney CD4⁺ T_RM cells from patients with ANCA-GN compared to kidney CD4⁺ T_RM cells from healthy controls. d, Violin plot showing ISR-associated gene scores based on the expression of PPP1R15A, PPP1R15B, ATF3, ATF4, ATF5, ATF6, DDIT3, DNAJB1, DUSP1, FOS, JUN, FOSB and JUNB in kidney CD4⁺ T_RM cells from patients with ANCA-GN and healthy controls. e, Violin plot showing cytokine-responsive gene scores based on transcriptome data of kidney biopsies from patients with ANCA-GN (n = 22) and healthy controls (n = 21)²⁶. f, UMAP plot showing the distribution of CD4⁺S1PR1⁻IL17A^hi T_RM cells, CD4⁺SELL⁻S1PR1⁻TNF^hi T_RM cells, CD4⁺SELL⁻S1PR1⁺ T_EM cells and CD4⁺SELL⁺S1PR1⁺ T_CM/T_N cells isolated from the colon of healthy controls (n = 2) and patients with Crohn’s disease (n = 2) (left) and heatmap showing the expression of KLF2, S1PR1, CCR7, SELL, RORC, IL17A, IL22 and TNF mRNA in CD4⁺ T_CM/T_N, T_EM, TNF^hi T_RM and IL17A^hi T_RM cells (right). g, Violin plot showing cytokine scores in colon CD4⁺TNF^hi and CD4⁺IL17A^hi T_RM cells from healthy controls and patients with Crohn’s disease as in f. h, Reactome analysis showing pathways downregulated in colon CD4⁺TNF^hi and CD4⁺IL17A^hi T_RM cells from patients with Crohn’s disease compared to colon CD4⁺TNF^hi and CD4⁺IL17A^hi T_RM cells from healthy controls as in f. i, Violin plots showing ISR-associated gene scores in colon CD4⁺TNF^hi and CD4⁺IL17A^hi T_RM cells from healthy controls and patients with Crohn’s disease as in f. j, Violin plot showing cytokine-responsive gene scores based on transcriptome data of colon biopsies from patients with Crohn’s disease (n = 92) and healthy controls (n = 55). Data are mean + s.e.m. Statistical analysis was performed using unpaired two-tailed t-test with Welch’s correction (d,e,i,j); **P < 0.01.