Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation Fayhan J. Alroqi, MD,

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Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation Fayhan J. Alroqi, MD, Louis-Marie Charbonnier, PhD, Safa Baris, MD, Ayca Kiykim, MD, Janet Chou, MD, Craig D. Platt, MD, PhD, Abdulrahman Algassim, MD, Sevgi Keles, MD, Bandar K. Al Saud, MD, Fowzan S. Alkuraya, MD, Michael Jordan, MD, Raif S. Geha, MD, Talal A. Chatila, MD, MSc Journal of Allergy and Clinical Immunology Volume 141, Issue 3, Pages 1050-1059.e10 (March 2018) DOI: 10.1016/j.jaci.2017.05.022 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 1050-1059 Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Clinical response of LRBA-deficient patients to CTLA4-Ig therapy. A and B, Body mass index (Fig 1, A) and platelet counts (Fig 1, B) of LRBA-deficient patients before and after treatment with CTLA4-Ig. C, Serum glucose levels and insulin use in patient P2: status after CTLA4-Ig therapy. D and E, High-resolution chest computed tomographic scans (Fig 1, D) and pulmonary function tests (Fig 1, E) of patient P3 before and after treatment with CTLA4-Ig. FVC, Forced vital capacity; TLC, total lung capacity. ****P < .0001, 2-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 TFH cell frequency in LRBA-deficient patients correlates with other markers of immune dysregulation. A, Flow cytometric analyses of CXCR5 and PD-1 expression in CD4+ T cells in LRBA-deficient patients before and after treatment with CTLA4-Ig. B-D, cTFH cell frequencies (Fig 2, B), serum sCD25 levels (Fig 2, C), and naive CD4+CD45RA+CCR7+ T-cell frequencies (Fig 2, D) in LRBA-deficient patients before and after treatment with CTLA4-Ig. E, Correlation between cTFH cell frequencies and sCD25 levels in LRBA-deficient patients. F, Flow cytometric analysis of ICOS and PD-1 expression on control cTFH cells and on patients' cTFH cells before and after CTLA4-Ig therapy. G, Relative mean fluorescence intensity (MFI) of ICOS and PD-1 expression on cTFH cells from patients versus control subjects. ***P < .001 and ****P < .0001, Student 2-tailed t test. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 cTFH cells of LRBA-deficient patients are skewed toward a TH1-like cell phenotype. A and B, Flow cytometric analyses of CXCR3 and CCR6 expression in cTFH cells of LRBA-sufficient and LRBA-deficient subjects before and after CTLA4-Ig treatment. C and D, Flow cytometric analyses of IL-17 and IL-21 expression (Fig 3, C, upper panels) or IFN-γ and IL-4 (Fig 3, C, lower panels) and the respective scatter plot representation (Fig 3, D) in cTFH cells of LRBA-sufficient and LRBA-deficient subjects before and after CTLA4-Ig treatment. *P < .05 and **P < .01, 1-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 TFH cell frequency in patients with CTLA4 deficiency and its response to CTLA4-Ig therapy. A and B, Flow cytometric analysis of CTLA4 expression on CD4+FOXP3+ Treg cells (Fig 4, A) and cTFH cells (Fig 4, B) of control (Ctrl) subjects and patients P7 and P8 with a heterozygous CTLA4 mutation. C, Correlation between cTFH cell frequencies and the mean fluorescence intensity (MFI) of CTLA4 expression in Treg cells of control (n = 8), LRBA-deficient (n = 6), and heterozygous CTLA4 mutant (n = 3) subjects. D, Flow cytometric analysis of CTLA4 expression on CD4+FOXP3+ cells in patient P9 with a heterozygous CTLA4 mutation. E, cTFH cells in patient P9 before and after CTLA4-Ig therapy. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Ineffective Treg cell control of TFH cell differentiation in LRBA-deficient subjects. A, Flow cytometric analysis of CXCR5 and ICOS expression in in vitro–differentiated iTFH-like cells of control and LRBA-deficient subjects. B and C, Mean fluorescence intensity (MFI) of ICOS expression in iTFH-like cells (Fig 5, B) and frequencies of in vitro–differentiated iTFH-like cells (Fig 5, C) derived from control and LRBA-deficient naive CD4+ T cells in the absence or presence of CTLA4-Ig. D and E, Flow cytometric analysis of PD-1 expression (Fig 5, D) and bar graph representation (Fig 5, E) of PD-1 expression in iTFH cells of control and LRBA-deficient subjects. F and G, Flow cytometric analysis (Fig 5, F) and frequencies (Fig 5, G) of in vitro–differentiated iTFH-like cells derived from control and LRBA-deficient naive CD4+ T cells in the absence or presence of anti-CTLA4 mAb and/or Treg cells from patients and control subjects. Results are representative of 2 independent experiments. *P < .05, **P < .01, and ***P < .001, 2-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Autoantibody production and cTFH cell function in LRBA-deficient subjects. A, Autoantibody production in LRBA-deficient patients before and after CTLA4-Ig therapy. Heat map showing IgG autoantibodies against self-antigens in sera of LRBA-deficient patients, healthy control subjects, patients with IPEX syndrome, and a patient with SLE. A value of 1 (black) is equal to the control average + 1 SD. Autoantibody responses affected by CTLA4-Ig therapy are boxed in red. B, IgM and IgG production in cocultures of cell-sorted cTFH and naive B cells derived from patient P3 and her HLA fully matched sister in the presence of Staphylococcal enterotoxin B (SEB). C, Flow cytometric analysis (Fig 6, C, upper panels) and scatter plot representation (Fig 6, C, lower panels) of CD27 and IgD expression on circulating B cells of control subjects and LRBA-deficient subjects before and after CTLA4-Ig treatment. *P < .05 and **P < .01, Student unpaired 2-tailed t test; ****P < .0001, 1-way ANOVA with posttest analysis. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 LRBA deficiency leads to profound immune dysregulation caused by defective Treg cell function. A, Pedigree of the LRBA-deficient patient P3. Generations are designated by Roman numerals (I-II), and subjects are designated by Arabic numerals. Double lines connecting parents indicate consanguinity. Probands in the respective families are indicated as II.1 to II.5. Squares, Male subjects; circles, female subjects; solid symbols, patient P3. B, Sanger sequencing analysis of LRBA cDNA in patient P3, showing deletion of exon 57. C, Western blot analysis of LRBA protein expression in lymphocytes of patient P3 compared with a healthy control subject. Blots were reprobed for dedicator of cytokinesis 8 as a positive control. D, LRBA expression in CD3+ T lymphocytes from a control subject (blue line) and LRBA-deficient patient P3 (red line). E, Timeline showing clinical features of LRBA deficiency in patient P3 and response to different kinds of therapy. F, Flow cytometric histogram plots of FOXP3, CD25, and CTLA4 expression in CD4+FOXP3+ T cells (solid line) and CD4+FOXP3− T cells (dotted line) from a control subject (blue line) and LRBA-deficient patient P3 (red line). The gray area represents control isotype staining. HC, Healthy control subject. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 A, LRBA expression in PBMCs from control subjects (blue line) and LRBA-deficient patient P4 (red line). The gray area represents control isotype staining. B, Flow cytometric histogram plots of CTLA4 expression in CD4+FOXP3+ T cells from a control subject (blue line) and LRBA-deficient patient P4 (red line). The gray area represents CD4+FOXP3− T cells from a control subject. Tconv, Conventional T cells. C, Flow cytometric analyses of CXCR5 and PD-1 expression in CD4+ T cells (upper panels) and CXCR3 and CCR6 expression among CXCR5+PD-1+CD4+ T cells (cTFH cells; lower panels) in an LRBA-sufficient subject (Ctrl) and patient P4. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A, LRBA expression in PBMCs from control subjects (blue line) and LRBA-deficient patients P5 and P6 (red line and green line, respectively). The gray area represents control isotype staining. B, Flow cytometric histogram plots of CTLA4 expression in CD4+FOXP3+ T cells from a control subject (blue line) and LRBA-deficient patients P5 and P6 (red line and green line, respectively). The gray area represents CD4+FOXP3− T cells from a control subject. Tconv, Conventional T cells. C, Flow cytometric analyses of CXCR5 and PD-1 expression in CD4+ T cells (upper panels) and CXCR3 and CCR6 expression among CXCR5+PD-1+CD4+ T cells (cTFH cells; lower panels) in an LRBA-sufficient subject (Ctrl) and patients P5 and P6. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 A, Sanger sequencing analysis of CTLA4 DNA in patients P7 and P8, showing a heterozygous nonsense mutation in exon 2 (c.226C>T, p. Q76X). B, Sanger sequencing analysis of CTLA4 DNA in patient P9, showing a heterozygous nonsense mutation in exon 2 (c.356T>G, p.L119R). Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Sorting strategy of naive CD4+ cells. A, Flow cytometric analysis of the purity of sorted naive CD4+ (CD45RA+CCR7+) cells. B, Representative CXCR5 and PD-1 expression in total CD4+ cells and cell-sorted naive CD4+ cells of a control subject and LRBA-deficient patient. Journal of Allergy and Clinical Immunology 2018 141, 1050-1059.e10DOI: (10.1016/j.jaci.2017.05.022) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions