CD8+CD28−CD127loCD39+ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection? Daniela Fenoglio, PhD, Chiara Dentone, MD,

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CD8+CD28−CD127loCD39+ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection? Daniela Fenoglio, PhD, Chiara Dentone, MD, Alessio Signori, PhD, Antonio Di Biagio, MD, Alessia Parodi, PhD, Francesca Kalli, PhD, Giorgia Nasi, PhD, Monica Curto, PhD, Giovanni Cenderello, MD, Pasqualina De Leo, MD, Valentina Bartolacci, MD, Giancarlo Orofino, MD, Laura Ambra Nicolini, MD, Lucia Taramasso, MD, Edoardo Fiorillo, PhD, Valeria Orrù, PhD, Paolo Traverso, MD, Bianca Bruzzone, MD, Federico Ivaldi, PhD, Eugenio Mantia, MD, Michele Guerra, MD, Simone Negrini, MD, Mauro Giacomini, Sanjay Bhagani, MD, FRCP, Gilberto Filaci, MD Journal of Allergy and Clinical Immunology Volume 141, Issue 6, Pages 2220-2233.e4 (June 2018) DOI: 10.1016/j.jaci.2017.08.021 Copyright © 2017 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 2220-2233 Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig 1 Frequency of Treg cell subsets in patients affected by HIV or HCV infection, patients with cancer, and healthy control subjects. CD8+CD28−CD127loCD39+ Treg cells and CD4+CD25hiCD127lo Treg cells were named CD8+ and CD4+ Treg cells in the figure, respectively. A, Comparison among the frequencies of CD8+CD28−CD127loCD39+ Treg cells in the circulation of healthy control subjects (HC), naive HIV-infected patients (Naïve HIV+), untreated HCV-monoinfected patients (HCV), patients with cancer (CP), and patients with tumor-infiltrating lymphocytes (TIL). B, Comparison between CD8+CD28−CD127loCD39+ and CD4+CD25hiCD127lo Treg cell frequencies in the circulation of healthy control subjects (HC) and naive HIV-infected patients (Naïve HIV+): CD8+ and CD4+ indicate CD8+CD28−CD127loCD39+ and CD4+CD25hiCD127lo Treg cells, respectively. C, Comparison of the sums of circulating CD8+CD28−CD127loCD39+ and CD4+CD25hiCD127lo Treg cell frequencies between healthy control subjects (HC) and naive HIV-infected patients (Naïve HIV+). D, Representative proliferation suppression assay performed with circulating CD8+CD28−CD127loCD39+ Treg cells purified from patient 24. The percentages of T-cell proliferation under unstimulated (left panel) or anti-CD3 UCHT1 mAb–stimulated (central and right panels) conditions are shown; in the right panel the percentage of proliferation inhibition by CD8+CD28−CD127loCD39+ Treg cells is shown in parentheses. The box shows the percentages of suppressive activity on T-cell proliferation achieved with sorted CD8+CD28−CD127loCD39+ Treg cells from patients 9, 17, and 24. All experiments were performed with autologous PBMCs as responder cells. CFSE, Carboxyfluorescein succinimidyl ester. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Correlation of CD8+CD28−CD127loCD39+ Treg cell frequency with HIV viremia, CD4+ T-cell percentages, and absolute CD4+ T-cell counts in naive HIV-infected patients. CD8+CD28−CD127loCD39+ Treg cells and CD4+CD25hiCD127lo Treg cells were named CD8+ and CD4+ Treg cells in this figure, respectively. Correlations were performed either considering only data collected before ART initiation (BASELINE; A and B) or data achieved at all the examined time points (ALL TIMEPOINTS, including baseline and 3, 6, 9, and 12 months after initiation of ART; C and D). Viremia is expressed as HIV RNA copies/mL on cube root transformation (c.r.). Fig 2, A, Correlations performed with data collected from all patients at baseline. Fig 2, B, Correlations performed with data collected only from stage A patients at baseline. Fig 2, C and D, Correlations performed with data collected from all patients at all time points (n = 158; baseline and 3, 6, 9, and 12 months after initiation of ART). Correlations were calculated by using the Pearson correlation coefficient. Viremia is expressed as HIV RNA copies/mL and represented on a log10 scale. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig 3 Analyses of Ki-67 expression on CD8+CD28−CD127loCD39+ cells and CD8+CD28−CD127loCD39+ Treg cell binding to HLA-A2 gag1-10 pentamers. A, Gating strategy to measure the fraction of Ki-67+ cells among CD8+CD28−CD127loCD39+ Treg cells from representative HIV-infected patient 72. Comparable findings were achieved in all tested HIV-infected patients. B, analysis of CD8+ T-cell and CD8+CD28−CD127loCD39+ Treg cell binding to HLA-A2 gag1-10 pentamers performed with cells from representative HIV-infected patient 56. Upper panels show HLA-A2 gag1-10 pentamer–positive CD8+CD28−CD127loCD39+ Treg cells within the total CD8+ T-cell subpopulation; lower panels show HLA-A2 gag1-10 pentamer–positive cells within the total CD8+ T-cell subpopulation. Percentages of positivity are indicated. The box shows the calculation for achieving the percentage of CD8+CD28−CD127loCD39+GAG+ Treg cells within the total CD8+GAG+ T-cell subpopulation. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig 4 Longitudinal assessment of CD8+CD28−CD127loCD39+ Treg cell frequencies, viremia, and CD4+ T-cell percentages and absolute counts. CD8+CD28−CD127loCD39+ Treg cells were named CD8+ Treg cells in the figure. Trends of the following biomarkers of disease in naive HIV-infected patients during 12 months of follow-up after ART initiation are shown, respectively (top to bottom side): CD8+CD28−CD127loCD39+ Treg cell frequency, viremia, CD4+ T-cell percentage, and CD4+ T-cell count. P values refer to the differences from baseline values during the entire follow-up. Predictions with CIs were estimated from a linear mixed model. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig 5 CD8+CD28−CD127loCD39+ Treg cell frequency in ECs, LTNPs, and naive HIV-infected patients. CD8+CD28−CD127loCD39+ Treg cells were named CD8+ Treg cells in the figure. Comparison among the CD8+CD28−CD127loCD39+ Treg cell frequencies in the circulation of ECs, LTNPs, and naive HIV-infected (Naïve HIV+) patients at baseline are shown. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig 6 Correlation between circulating frequencies of CD8+CD28−CD127loCD39+ Treg cells and activated CD8+ T lymphocytes. CD8+CD28−CD127loCD39+ Treg cells were named CD8+ Treg cells in the figure. A, Correlation between CD8+CD28−CD127loCD39+ Treg cell and CD8+CD38+ T-lymphocyte frequencies in the circulation of naive HIV-infected patients. Data were collected before and after initiation of ART at different time points. B, Correlation between CD8+CD28−CD127loCD39+ Treg cell and CD8+CD38+DR+ T-lymphocyte frequencies in the circulation of naive HIV-infected patients. Data were collected before and after instauration of ART at different time points. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig E1 Expression of CCR2 and CCR4 chemokine receptors by CD8+CD28−CD127loCD39+ Treg cells from representative patient 14. Comparable findings were achieved in all tested HIV-infected patients. Percentages of CD8+CD28−CD127loCD39+ Treg cells positive for the 2 chemokine receptors are shown in the respective boxes of plotting. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig E2 Comparison between suppression activity of CD4+CD25hiCD127lo Treg cells from a healthy donor and that of CD8+CD28−CD127loCD39+ Treg cells from representative HIV-infected patient 21. CFSE, Carboxyfluorescein succinimidyl ester. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions

Fig E3 Longitudinal analyses of CD8+CD28+CD127loCD39+ Treg cell frequencies and viremia in representative patients 16, 21, 22, and 25. Journal of Allergy and Clinical Immunology 2018 141, 2220-2233.e4DOI: (10.1016/j.jaci.2017.08.021) Copyright © 2017 The Authors Terms and Conditions