Cytotoxic CD8+ T cells target citrullinated antigens in rheumatoid arthritis

doi:10.1038/s41467-022-35264-8

. 2023 Jan 19;14(1):319.

doi: 10.1038/s41467-022-35264-8.

Cytotoxic CD8⁺ T cells target citrullinated antigens in rheumatoid arthritis

Jae-Seung Moon^#^{1

2}, Shady Younis^#^{1

2

3}, Nitya S Ramadoss^{1

2}, Radhika Iyer^{1

2}, Khushboo Sheth^{1

2}, Orr Sharpe^{1

2}, Navin L Rao⁴, Stephane Becart⁵, Julie A Carman⁴, Eddie A James⁶, Jane H Buckner⁶, Kevin D Deane⁷, V Michael Holers⁷, Susan M Goodman^{8

9}, Laura T Donlin^{8

9}, Mark M Davis^{3

10}, William H Robinson^{11

12

13}

Affiliations

¹ Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
⁴ Immunology Discovery, Janssen Research and Development LLC, Spring House, PA, 19477, USA.
⁵ Immunology Discovery, Janssen Research and Development LLC, San Diego, CA, 92121, USA.
⁶ Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA.
⁷ Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
⁸ Hospital for Special Surgery, New York, NY, 10021, USA.
⁹ Weill Cornell Medicine, New York, NY, 10021, USA.
¹⁰ Department of Microbiology and Immunology, Stanford University, Stanford, CA, 94305, USA.
¹¹ Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. w.robinson@stanford.edu.
¹² VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA. w.robinson@stanford.edu.
¹³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. w.robinson@stanford.edu.

^# Contributed equally.

PMID: 36658110
PMCID: PMC9852471
DOI: 10.1038/s41467-022-35264-8

Cytotoxic CD8⁺ T cells target citrullinated antigens in rheumatoid arthritis

Jae-Seung Moon et al. Nat Commun. 2023.

. 2023 Jan 19;14(1):319.

doi: 10.1038/s41467-022-35264-8.

Authors

Affiliations

¹ Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA.
² VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA.
³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
⁴ Immunology Discovery, Janssen Research and Development LLC, Spring House, PA, 19477, USA.
⁵ Immunology Discovery, Janssen Research and Development LLC, San Diego, CA, 92121, USA.
⁶ Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, 98101, USA.
⁷ Division of Rheumatology, University of Colorado Anschutz Medical Campus, Aurora, CO, 80045, USA.
⁸ Hospital for Special Surgery, New York, NY, 10021, USA.
⁹ Weill Cornell Medicine, New York, NY, 10021, USA.
¹⁰ Department of Microbiology and Immunology, Stanford University, Stanford, CA, 94305, USA.
¹¹ Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, 94305, USA. w.robinson@stanford.edu.
¹² VA Palo Alto Health Care System, Palo Alto, CA, 94304, USA. w.robinson@stanford.edu.
¹³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA. w.robinson@stanford.edu.

^# Contributed equally.

PMID: 36658110
PMCID: PMC9852471
DOI: 10.1038/s41467-022-35264-8

Abstract

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8⁺ T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8⁺ T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB⁺CD8⁺ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK⁺CD8⁺ memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB⁺CD8⁺ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB⁺CD8⁺ cells are present in RA synovium. These findings suggest that cytotoxic CD8⁺ T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Increased levels of CD8⁺ T cells expressing cytotoxic mediators in the blood of ACPA+ RA patients.**
a Frequency of CD8⁺ T cells among total lymphocytes in PBMCs from healthy controls (HC; n = 30), ACPA− RA (n = 14), and ACPA+ RA (n = 45) measured by flow cytometry (^*P = 0.0179, or ^***P = 0.0001). b Spearman’s correlation between the ratio of CD8⁺ T cells and serum anti-CCP antibody (surrogate for ACPA) levels in RA (n = 39; R = 0.5434, P = 0.0004). **c–e** Percentage of CD69, GPR56, or TCRγδ-expressing CD8⁺ T cells: HC (n = 30), ACPA− RA (n = 14), and ACPA+ RA (n = 45). For c, ^*P = 0.0355, or ^*P = 0.0233. For d, ^*P = 0.0231. For e, ^*P = 0.0120, or ^*P = 0.0237. f Representative flow cytometry results (*upper*) and quantified graphs (*lower*) of GzmB, or GzmK expressing CD8⁺ T cells in HC (n = 9 for GzmK, or 11 for GzmB) and ACPA+ RA (n = 10 for GzmK, or 11 for GzmB). For GzmB⁺CD8⁺ T cells, ^**P = 0.0014. g Flow cytometry analysis of memory subsets of CD8⁺ T cells: CCR7^hiCD45RA^hi (Naïve), CCR7^hiCD45RA^low (CM, Central memory), CCR7^lowCD45RA^low (EM, Effector memory), CCR7^lowCD45RA^hi (EMRA, Effector Memory cells Re-expressing CD45RA) (*upper*). Quantified proportion of each memory subset in HC (n = 30), ACPA− RA (n = 14), or ACPA+ RA (n = 45) patients (*lower*). In N, ^**P = 0.004, or ^***P < 0.001. In EM, ^*P = 0.03. In EMRA, ^***P < 0.001. Data are presented as means ± SEM. ^*P < 0.05, ^**P < 0.01, or ^***P < 0.001 by ordinary one-way ANOVA (a, c–f), and two-way ANOVA (g) with Tukey’s multiple comparisons test. ns, not significant. Source data are provided as a Source Data file. ACPA anti-citrullinated protein antibodies, RA rheumatoid arthritis, CCP cyclic citrullinated peptide, GzmB Granzyme B, GzmK Granzyme K.

**Fig. 2. Transcriptional landscape of CD8⁺ T cells in ACPA+ RA and HC blood.**
Single cell RNA-seq of CD8⁺ T cells in ACPA+ RA (n = 12) and healthy (n = 6) PBMC samples using the 10X Genomics Chromium platform. a UMAP plot of 7 annotated clusters from CD8⁺ T cells (n = 16,000) in ACPA+ RA and healthy PBMC samples. b Density of mRNA expression of the key markers for CD8⁺ T cells clusters. c Distribution of CD8⁺ T cells from ACPA+ RA and HC in each cluster. d Dot plot of enrichment analysis of pseudobulk differentially expressed genes (DEGs) between *GZMB*⁺ clusters in ACPA+ RA and HC cells (red) or *GZMK*⁺ clusters in ACPA+ RA and HC cells (blue). The calculated log2 fold-change of gene expression in ACPA+ RA vs HC were multiplied by the -log (FDR) and the output values were used to rank the genes descending and perform gene-set enrichment analysis (GSEA) in *GZMB*⁺ or *GZMK*⁺ clusters independently. Numbers in the circle indicate the normalized enrichment score (NES) for each pathway in *GZMB*⁺ (red) or *GZMK*⁺ (blue). Adjusted P value (p.adj) for multiple testing using Benjamini–Hochberg. e Enrichment GO analysis of cell killing pathway of upregulated genes in *GZMB*⁺ (ACPA+ RA vs HC) or *GZMK*⁺ (ACPA+ RA vs HC). f Heatmap of normalized pseudobulk expression of genes involved in the cell killing and T cell cytotoxicity enrichment pathway. Each column represents one pseudobulk expression of one sample of the indicated clusters. g The direct comparison of key cytotoxic genes and their differential expressions across *GZMB*⁺ vs *GZMK*⁺ clusters in ACPA+ RA (n = 12) and HC (n = 6) CD8⁺ T cells. P values of Wilcox test are presented on the top of each comparison. The boxplot represents the median shown as a line in the center of the box, the boundaries are the first and third quartile, and whiskers represent the minimum and maximum values in the data. Source data are provided as a Source Data file. HC healthy control, ACPA anti-citrullinated protein antibodies, RA rheumatoid arthritis, DE differentially expressed, GO gene ontology.

**Fig. 3. Single-cell transcriptomics and TCR sequencing demonstrate clonally expanded CD8⁺ T cells expressing cytotoxic mediators in ACPA+ RA blood.**
a UMAP plots of healthy (n = 6) or ACPA+ RA (n = 12) CD8⁺ T cells integrated with TCR clonality (n = 10,400 paired *TCRαβ* sequences). Color indicates the groups by the frequency of clonotypes in total cells. X represents the frequency of each clonotype defined by its unique paired *TCRαβ* sequence. Large-expanded clones (X > 20), Medium-expanded clones (20 > X ≧ 5), Small expanded clones (5 > X ≧ 2), and Singletons (X = 1). Cells lacking *TCRαβ* sequence information were designated as NA (Not Applicable in this analysis). b Proportion of clonal lineages based on clonal size in each cluster. c Bar plots comparing the percentage of clonally expanded cells in *GZMB* (*left*) or *GZMK* (*right*)-expressing clusters between ACPA+ RA and HC. d Bar plots of absolute numbers of T cell clones in *GZMB*⁺ and *GZMK*⁺ clusters. e Heatmap of select gene markers and pathways expressed by clonally expanded and singleton CD8⁺ T cells in ACPA+ RA and HCs. Top bars indicate clonal size, patients /disease state, clusters, patient sample ID and quality control metric. Individual T cells are ordered by clonal size. Source data are provided as a Source Data file. HC healthy control, ACPA anti-citrullinated protein antibodies, RA rheumatoid arthritis, TCR T cell receptor.

**Fig. 4. CD8⁺ T cells in ACPA+ RA blood proliferate in response to citrullinated antigens.**
a, b PBMCs (5 × 10⁵) of ACPA+ RA patients were incubated with anti-CD3/28 antibodies (n = 14), NP (influenza A)/ pp65 (CMV) protein (50 μM of each, n = 14), native vimentin protein (100 μM, n = 5), or citrullinated vimentin (cit-vimentin) protein (100 μM, n = 14) with or without anti-CD8 and/or HLA class I-blocking antibody (anti-CD8 Ab n = 6, anti-HLA class I Ab n = 6 or anti-CD8/ HLA class I Abs n = 10), or no stimulation (n = 15) for 3 days. The percentage of Ki-67-expressing CD8⁺ (a) or CD4⁺ (b) T cells in ACPA+ RA PBMCs was measured by flow cytometry. For a, ^***P < 0.0001, ^**P = 0.026, ^**P = 0.0021, ^#P = 0.0471, ^#P = 0.026, ^##P = 0.0056 or ^##P = 0.0021^. For b, ^***P < 0.0001, or ^*P = 0.0383. c, d Native vimentin or cit–vimentin pulsed monocyte-derived dendritic cells (MoDCs) were cocultured with Cell Proliferation Dye eF450-labeled CD3⁺ T cells isolated from ACPA+ RA PBMCs (n = 9) with or without anti-CD8/HLA class I-blocking antibody for 10 days, followed by flow cytometry analysis. Representative flow cytometry results (c, *left*) and quantification of the percentage of dye^low proliferating CD8⁺ T cells (c, *right*) or CD4⁺ T cells (d). For c, ^***P < 0.0001, ^**P = 0.0054, ^**P = 0.0015, ^#P = 0.0494 or ^#P = 0.0251. For d, ^***P < 0.0001, ^*P = 0.0171, or ^#P = 0.0484. e Proliferation capacity of ACPA⁺ RA CD8⁺ T cells based on proliferation dye eF450-labeled CD8⁺ T cells co-cultured with cit-vimentin or native vimentin-loaded MoDCs in the absence or presence of anti-CD8/HLA class I-blocking antibody for 10 days (n = 4). ^**P = 0.0011, ^**P = 0.0027, ^#P = 0.0486, or ^###P = 0.0007. Representative histograms (*left*) and quantification of the proliferating CD8⁺ T cells (*right*). Bars represent means ± SEM. *P < 0.05, **P < 0.01, or ***P < 0.001 versus no treatment by unpaired t-test with two-tailed test; and ^#P < 0.05, ^##P < 0.01, or ^###P < 0.001 versus cit-vimentin treatment by unpaired t-test with two-tailed test. Source data are provided as a Source Data file. HC healthy control, ACPA anti-citrullinated protein antibodies, RA rheumatoid arthritis, Cit-Vim citrullinated vimentin.

**Fig. 5. Citrullinated antigens induce clonal expansion of ACPA+ RA blood CD8⁺ T cells that express cytotoxic and synovial-trafficking markers.**
a, b UMAP plots showing clonal size of ACPA+ RA CD8⁺ T cells (n = 3284) stimulated by vimentin or citrullinated vimentin (a) and H3 or citrullinated H3 (b). c Cytotoxicity and RA synovial-trafficking scores in CD8⁺ T cells stimulated by native or citrullinated antigens. **d, e** Comparison of TCR repertoire in CD8⁺ T cells stimulated by native or citrullinated proteins (Vimentin; d or H3; e). Bar graphs representing changes of proportion in each top 5 clonotype between native and citrullinated antigens (*left*), UMAP depicting the selected 5 expanded clones labeled by different color (*right*). f Expression level of *GZMB*, *GNLY*, *IFNG*, *GZMK* or *MKI67* in the selected 5 clonotypes stimulated by native vimentin (n = 9) or citrullinated vimentin (n = 67). The boxplot represents the median shown as a line in the center of the box, the boundaries are the first and third quartile, and whiskers represent the minimum and maximum values in the data. g, h Integrated analysis of paired blood and synovial tissue using single cell RNA seq datasets to identify whether RA synovial cytotoxic CD8⁺ T cells express transcriptional programs shared with those expressed by the citrullinated antigen-reactive clonally expanded *GZMB*⁺*GNLY*⁺ CD8⁺ T cells in RA blood. Circos plot depicting shared expanded clonal families in PBMCs (red) or synovium (blue) from two representative ACPA+ RA patients distinguished by brown and gray colors (g). Heatmap showing expression level of cytotoxic markers such as *GZMB*, *GNLY* or *GZMK* in each expanded clone of blood or synovium (h). In f, ^*P < 0.05, or ^***P < 0.001 by two-tailed unpaired t-test (*GZMB*; ^***P = 0.00054, *GNLY*; ^*P = 0.024, *IFNG*; ^*P = 0.014, *GZMK*; P = 0.3209, *MKI67*; ^*P = 0.016). ns, not significant. Source data are provided as a Source Data file. ACPA anti-citrullinated protein antibodies, RA rheumatoid arthritis.

**Fig. 6. ACPA+ RA blood CD8⁺ T cells upregulate activation and cytotoxic markers in response to citrullinated antigens.**
a Stimulation of fresh blood from ACPA+ RA (n = 8, red bars) or HCs (n = 7, blue bars) with anti-CD3/28 Abs, NP/pp65, cit- or native vimentin for 6 h with addition of Golgi inhibitor for the last 5 h. Quantification of CD69⁺ and GzmB⁺IFNγ⁺ CD8⁺ T cells, and IFNγ⁺ CD4⁺ T cells. For CD69⁺CD8⁺, ^*P = 0.049, ⁺P = 0.0397, ^**P = 0.001, ^##P = 0.009, or ^###P = 0.0008. For GzmB⁺IFNγ⁺CD8⁺, ⁺P = 0.0175, ^**P = 0.0071, ^##P = 0.0071, or ^##P = 0.0037. For IFNγ⁺CD4⁺, ⁺⁺P = 0.0065, ⁺P = 0.0489, ^*P = 0.0155, ^#P = 0.0351, or ^##P = 0.0038. b PBMCs of ACPA+ RA patients (n = 10) were incubated with anti-CD3/28 Abs, NP/pp65 (50 μM of each), individual citrullinated proteins (100 μM), all citrullinated proteins (20 μM each), or all native proteins (20 μM each) for 16 h. Percentage of IFNγ or Granzyme B (GzmB) expressing CD8⁺ T cells measured by intracellular staining. c Quantification of IFNγ⁺ or GzmB⁺IFNγ⁺ expressing CD8⁺ T cells in ACPA+ RA PBMCs treated with cit- or native vimentin in a dose-dependent manner (1, 10 or 100 μM) (n = 7). d Quantitative analysis of IFNγ⁺ or GzmB⁺IFNγ⁺ expressing CD8⁺ T cells in ACPA+ RA PBMCs stimulated with cit-vimentin in the presence or absence of anti-CD8 and/or HLA class I-blocking antibody (n = 10). Data are presented as means ± SEM. For a, two-tailed unpaired t-test: ^*P < 0.05 or ^**P < 0.01 versus no treatment in ACPA+ RA; ⁺P < 0.05, or ⁺⁺P < 0^.01 versus no treatment in HC; and ^#P < 0.05, ^##P < 0.01, or ^###P < 0.001 versus cit-vimentin in ACPA⁺ RA. For b, two-tailed unpaired t-test: ^*P < 0.05, ^**P < 0.01, or ^***P < 0.001 versus no treatment; ^#P < 0.05, or ^##P < 0.01 versus all native proteins. For c, two-tailed unpaired t-test: *P < 0.05, or **P < 0.01 versus no treatment; ^#P < 0.05 for cit-vimentin 1 μM versus vimentin 1 μM; ^$P < 0.05 for cit-vimentin 10 μM versus native vimentin 10 μM by two-tailed unpaired t-test; ⁺P < 0^.05 for cit-vimentin 100 μM versus native vimentin 100 μM. For d, by two-tailed unpaired t-test: *P < 0.05, or **P < 0.01 versus no treatment; ^#P < 0.05, or ^##P < 0.01 versus cit-vimentin 100 μM. Source data are provided as a Source Data file. HC healthy control, ACPA anti-citrullinated protein antibodies, RA rheumatoid arthritis, Cit-Vim citrullinated vimentin.

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Comment in

Citrulline immunity in RA: CD8⁺ T cells enter the scene.
Chemin K, Malmström V. Chemin K, et al. Nat Rev Rheumatol. 2023 May;19(5):259-260. doi: 10.1038/s41584-023-00945-1. Nat Rev Rheumatol. 2023. PMID: 36914789 No abstract available.

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References

1. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46:183–196. doi: 10.1016/j.immuni.2017.02.006. - DOI - PMC - PubMed
1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 2011;365:2205–2219. doi: 10.1056/NEJMra1004965. - DOI - PubMed
1. Vander Cruyssen B, et al. Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: specificity and relation with rheumatoid factor. Autoimmun. Rev. 2005;4:468–474. doi: 10.1016/j.autrev.2005.04.018. - DOI - PubMed
1. Schellekens GA, De Jong B, Van den Hoogen F, Van de Putte L, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Investig. 1998;101:273–281. doi: 10.1172/JCI1316. - DOI - PMC - PubMed
1. György B, Tóth E, Tarcsa E, Falus A, Buzás EI. Citrullination: a posttranslational modification in health and disease. Int. J. Biochem. Cell Biol. 2006;38:1662–1677. doi: 10.1016/j.biocel.2006.03.008. - DOI - PubMed

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[1] Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46:183–196. doi: 10.1016/j.immuni.2017.02.006. - DOI - PMC - PubMed

[2] Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis. Immunity. 2017;46:183–196. doi: 10.1016/j.immuni.2017.02.006. - DOI - PMC - PubMed

[3] McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 2011;365:2205–2219. doi: 10.1056/NEJMra1004965. - DOI - PubMed

[4] McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 2011;365:2205–2219. doi: 10.1056/NEJMra1004965. - DOI - PubMed

[5] Vander Cruyssen B, et al. Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: specificity and relation with rheumatoid factor. Autoimmun. Rev. 2005;4:468–474. doi: 10.1016/j.autrev.2005.04.018. - DOI - PubMed

[6] Vander Cruyssen B, et al. Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: specificity and relation with rheumatoid factor. Autoimmun. Rev. 2005;4:468–474. doi: 10.1016/j.autrev.2005.04.018. - DOI - PubMed

[7] Schellekens GA, De Jong B, Van den Hoogen F, Van de Putte L, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Investig. 1998;101:273–281. doi: 10.1172/JCI1316. - DOI - PMC - PubMed

[8] Schellekens GA, De Jong B, Van den Hoogen F, Van de Putte L, van Venrooij WJ. Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Investig. 1998;101:273–281. doi: 10.1172/JCI1316. - DOI - PMC - PubMed

[9] György B, Tóth E, Tarcsa E, Falus A, Buzás EI. Citrullination: a posttranslational modification in health and disease. Int. J. Biochem. Cell Biol. 2006;38:1662–1677. doi: 10.1016/j.biocel.2006.03.008. - DOI - PubMed

[10] György B, Tóth E, Tarcsa E, Falus A, Buzás EI. Citrullination: a posttranslational modification in health and disease. Int. J. Biochem. Cell Biol. 2006;38:1662–1677. doi: 10.1016/j.biocel.2006.03.008. - DOI - PubMed

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Cytotoxic CD8⁺ T cells target citrullinated antigens in rheumatoid arthritis

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Cytotoxic CD8⁺ T cells target citrullinated antigens in rheumatoid arthritis

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