CD4+ T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion Theresa Frenz, PhD, Elena Grabski, PhD, Daniela.

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CD4+ T cells in patients with chronic inflammatory rheumatic disorders show distinct levels of exhaustion Theresa Frenz, PhD, Elena Grabski, PhD, Daniela Buschjäger, MSc, Lea A.I. Vaas, PhD, Nina Burgdorf, Reinhold E. Schmidt, MD, Torsten Witte, MD, Ulrich Kalinke, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 2, Pages 586-589.e10 (August 2016) DOI: 10.1016/j.jaci.2016.04.013 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 In patients with rheumatic diseases, T cells show functional exhaustion. A, Activation marker expression of CD3+CD4+ T cells in PBMCs from healthy donors (control), patients with RA, and patients with SpA. B-D, Upon anti-CD3/anti-CD28 bead stimulation, intracellular IL-2 expression (Fig 1, B) and cell viability (Fig 1, D) were analyzed 24 hours after stimulation, and proliferation (Fig 1, C) was assessed 5 days after stimulation. E, PD-1/ICOS expression of CD3+CD4+ T cells in synovial fluid of patients with SpA (n = 3). F, Mean values of different entities: healthy subjects (gray), patients with RA (red), and patients with SpA (blue) normalized to healthy control subjects. G, Pearson correlation coefficient analysis in combination with unsupervised clustering for investigated variables (only correlations with P < .05): blue circles, positive correlation; red circles, negative correlation (n = 30 per group). *P < .05 and ***P < .0005. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 PD-1/CTLA-4 blocking can revert T-cell exhaustion. A, IL-2 expression of CD3+CD4+ T cells 24 hours later with or without anti–PD-1 antibody (n = 5 patients with RA and n = 7 patients with SpA). B, PD-1 expression on T cells shown in Fig 2, A, from treatment responders (red) compared with those from treatment nonresponders (black). C and D, ICOS/CD25/CTLA-4 expression (Fig 2, C) and IL-2 expression (Fig 2, D) and percentage of PI+ T cells 24 hours and proliferation 5 days after stimulation of PBMCs from control subjects or patients with RA treated with or without abatacept (n = 8 patients with RA with abatacept and n = 30 patients with RA without abatacept, control subjects). *P < .05, **P < .001, and ***P < .0005. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 CD69 and CD25 surface marker expression and percentage of CD45RO+ T cells within CD4+ T cells from patients with rheumatic disorders compared with healthy control subjects. The expression (mean fluorescence intensity [MFI]) of CD69 and CD25 of CD4+ T cells derived from patients with rheumatic disorders is indicated and compared with that in healthy donor CD4+ T cells. The percentage of CD45RO+ memory T cells within the CD4+ T-cell compartment is indicated. Staining was performed directly after isolation. Individual analysis and the mean of 30 donors per group are shown. For statistical analysis, an unpaired Student t test with a Welch correction was used: *P < .05, **P < .001, and ***P < .0005. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Correlation analysis between disease activity and PD-1/CTLA-4/CD25 expression or anti–TNF-α treatment and cytokine expression. A, Expression of PD-1, CTLA-4, and CD25 denoted in mean fluorescence intensity (MFI) were compared with DAS28 scores of patients with RA. No correlation of PD-1, CTLA-4, and CD25 expression and disease score was observed. B and C, Cytokine expression of IL-2, IFN-γ, and TNF-α (Fig E2, B) or PI+ dead cell numbers among CD4+ T cells (Fig E2, C) were determined at 24 hours on anti-CD3/anti-CD28 bead stimulation. D, Proliferation of CD4+ T cells at 120 hours on anti-CD3/anti-CD28 bead stimulation. E, PD-1 expression of freshly isolated CD4+ T cells within PBMCs denoted in MFI. Patients with RA and those with SpA treated with anti–TNF-α agents (+) and patients treated otherwise (−) were compared. For statistical analysis, an unpaired Student t test with the Welch correction was used: *P < .05, **P < .001, and ***P < .0005. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Proliferation of CD4+ T cells from patients with rheumatic disorders compared with healthy control subjects on TCR-independent stimulation. PBMCs were stimulated for 5 days with 1 μg/mL pertussis toxin. PKH-26 dilution as a measure of proliferation is indicated (n = 30 donors per group). For statistical analysis, an unpaired Student t test with a Welch correction was used: *P < .05. ns, Not significant. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Radial plot analysis of different analyzed entities. A, Radial plot analysis of different analyzed entities with SDs. Radial plots illustrate analyzed entities of patients with RA (red) and patients with SpA (blue), as well as healthy control subjects (gray). Normalization: Mean values of analyzed entities of patients were normalized against the corresponding mean values of healthy subjects (n = 30 per group). B and C, Radial plots illustrate analyzed entities of patients with RA (red) and patients with SpA (blue) comparing anti–TNF-α treatment with other treatments (Fig E4, B) or old (>60 years) with young (<60 years) patients (Fig E4, C). The old/young age distribution was 18/12 for patients with RA and 6/24 for patients with SpA. Normalization: Mean values of analyzed entities of patients were normalized against the corresponding mean values of healthy control subjects (n = 30 per group). D, Principal component analysis of different analyzed entities. Results obtained for surface marker expression of PD-1, CTLA-4, ICOS, OX40, CD25, and CD69; intracellular cytokine production (IL-2 and TNF-α); proliferation; and AICD of CD4+ T cells with PBMCs are shown. Principal components are compared for patients with RA (red), patients with SpA (blue), and healthy control subjects. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Radial plot analysis of different analyzed entities. A, Radial plot analysis of different analyzed entities with SDs. Radial plots illustrate analyzed entities of patients with RA (red) and patients with SpA (blue), as well as healthy control subjects (gray). Normalization: Mean values of analyzed entities of patients were normalized against the corresponding mean values of healthy subjects (n = 30 per group). B and C, Radial plots illustrate analyzed entities of patients with RA (red) and patients with SpA (blue) comparing anti–TNF-α treatment with other treatments (Fig E4, B) or old (>60 years) with young (<60 years) patients (Fig E4, C). The old/young age distribution was 18/12 for patients with RA and 6/24 for patients with SpA. Normalization: Mean values of analyzed entities of patients were normalized against the corresponding mean values of healthy control subjects (n = 30 per group). D, Principal component analysis of different analyzed entities. Results obtained for surface marker expression of PD-1, CTLA-4, ICOS, OX40, CD25, and CD69; intracellular cytokine production (IL-2 and TNF-α); proliferation; and AICD of CD4+ T cells with PBMCs are shown. Principal components are compared for patients with RA (red), patients with SpA (blue), and healthy control subjects. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Radial plot analysis of different analyzed entities. A, Radial plot analysis of different analyzed entities with SDs. Radial plots illustrate analyzed entities of patients with RA (red) and patients with SpA (blue), as well as healthy control subjects (gray). Normalization: Mean values of analyzed entities of patients were normalized against the corresponding mean values of healthy subjects (n = 30 per group). B and C, Radial plots illustrate analyzed entities of patients with RA (red) and patients with SpA (blue) comparing anti–TNF-α treatment with other treatments (Fig E4, B) or old (>60 years) with young (<60 years) patients (Fig E4, C). The old/young age distribution was 18/12 for patients with RA and 6/24 for patients with SpA. Normalization: Mean values of analyzed entities of patients were normalized against the corresponding mean values of healthy control subjects (n = 30 per group). D, Principal component analysis of different analyzed entities. Results obtained for surface marker expression of PD-1, CTLA-4, ICOS, OX40, CD25, and CD69; intracellular cytokine production (IL-2 and TNF-α); proliferation; and AICD of CD4+ T cells with PBMCs are shown. Principal components are compared for patients with RA (red), patients with SpA (blue), and healthy control subjects. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 A, Upon infection with pathogens, CD4+ T cells are activated by TCR triggering plus second signals of activating receptors, such as CD28 interacting with CD80/CD86. This activation leads to T-cell proliferation and cytokine expression. Upregulation of the inhibitory receptor CTLA-4, which binds CD80/CD86 with higher affinity than CD28, confers T-cell inhibition and cell death to downmodulate the T-cell response. B, In patients with chronic inflammatory diseases, constant antigen triggering causes T-cell exhaustion. On ex vivo stimulation, exhausted T cells show less proliferation and less cytokine expression but increased cell death on TCR stimulation. Blocking CD80/CD86 with abatacept treatment reverts T-cell exhaustion in patients with RA while preventing autoimmunity by reconstituting the equilibrium of T-cell activation and inhibition. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Random forest analysis for model building. For model building, the application of the package randomForestE5 and functionality therein provided 2 measures of importance for the investigated variables: mean decrease in accuracy and mean decrease in node impurity (see the Methods section for further details). Based on this, information models were manually built, aiming for the sparsest model while minimizing the AIC. Journal of Allergy and Clinical Immunology 2016 138, 586-589.e10DOI: (10.1016/j.jaci.2016.04.013) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions