Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity

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Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity Jared H. Rowe, MD, PhD, Brian D. Stadinski, PhD, Lauren A. Henderson, MD, Lisa Ott de Bruin, MD, Ottavia Delmonte, MD, Yu Nee Lee, PhD, M. Teresa de la Morena, MD, Rakesh K. Goyal, MD, Anthony Hayward, MD, PhD, Chiung-Hui Huang, PhD, Maria Kanariou, MD, Alejandra King, MD, Taco W. Kuijpers, MD, Jian Yi Soh, MD, Benedicte Neven, MD, PhD, Jolan E. Walter, MD, PhD, Eric S. Huseby, PhD, Luigi D. Notarangelo, MD Journal of Allergy and Clinical Immunology Volume 140, Issue 6, Pages 1739-1743.e7 (December 2017) DOI: 10.1016/j.jaci.2017.08.001 Copyright © 2017 Terms and Conditions

Fig 1 Flow cytometric and repertoire analysis of peripheral blood lymphocyte populations in patients with RAG mutations. A, Gating strategy for circulating CD4+, CD8+, and CD19+ lymphocytes (top) and relative proportions (bottom) in controls and RAG-mutated patients. B, Identification (top) and frequency (bottom) of Treg cells among CD4+ lymphocytes by CD25 and CD127 expression. C, FOXP3 expression in CD4+CD25hiCD127lo Treg cells (black line) and CD4+CD25−CD127+ Tconv cells (gray fill) from controls or patients (top). Geometric mean fluorescent intensity of FOXP3 protein expression in controls and patients with CID/AS (bottom). D, Unique TRB productive rearrangements for each subject's T-cell subpopulation. Shannon's H Entropy (E) and Simpson (F) index of diversity for productive TRB rearrangements. Frequency of 100 most abundant productive TRB clonotypes identified in Treg (G), CD4+ Tconv (H), and CD8+ (I) cells for patients (P1-P8) and controls (C1-C8). Representative heat maps depicting TRBV (rows) and TRBJ (columns) gene pairing in unique productive TRB rearrangements in Treg (J), Tconv (K), or CD8+ T cells (L) (5′ to 3′ orientation of V and J genes). ND, Not done. Student t test (Gaussian distribution) or Mann-Whitney test (non-Gaussian distribution) was used for flow cytometric statistical analysis and 2-way ANOVA was used for repertoire analysis with *P < .05, **P < .01, ***P < .001, and ****P < .0001. Bars represent mean ± SD. Journal of Allergy and Clinical Immunology 2017 140, 1739-1743.e7DOI: (10.1016/j.jaci.2017.08.001) Copyright © 2017 Terms and Conditions

Fig 2 Molecular characteristics of CDR3 of productive TRB rearrangements. Virtual spectratyping of CDR3 nucleotide length (top) and mean CDR3 length (bottom) of unique rearranged products in Treg (A), CD4+ Tconv (B), and CD8+ T (C) cells from controls and patients. TRB-CDR3 sequence homology at the nucleotide (top) and amino acid (bottom) level in different T-cell subsets (D-F). Self-reactivity index of Treg, Tconv, and CD8+ cells from all RAG-mutated patients (left), patients with CID/AS (middle), or patients with OS (right) compared with equivalent control subpopulations (G). ns, Not significant. Student t test was used for statistical analysis with *P < .05, **P < .01, ***P < .001, and ****P < .0001. In panels A-F, bars represent mean ± SD. **P < 10−10. Journal of Allergy and Clinical Immunology 2017 140, 1739-1743.e7DOI: (10.1016/j.jaci.2017.08.001) Copyright © 2017 Terms and Conditions

Fig E1 High throughput sequencing (HTS) of TRB repertoire in Treg, CD4+ Tconv, and CD8+ T-cell subsets. A, Gating strategy for fluorescent activated cell sorting to purify CD8+ T cells, CD4+ Treg cells, and CD4+ Tconv cells for HTS. B, Total number of HTS reads of productive TRB rearrangements identified in each subject for Treg, Tconv, and CD8+ T cells. Journal of Allergy and Clinical Immunology 2017 140, 1739-1743.e7DOI: (10.1016/j.jaci.2017.08.001) Copyright © 2017 Terms and Conditions

Fig E2 Heat maps depicting TRBV (shown in rows) and TRBJ (shown in columns) gene pairing in unique productive TRB rearrangements in CD4+ Treg, CD4+ Tconv, and CD8+ T cells from healthy controls (C1-C4) and RAG-mutated patients presenting with CID/AS (P1-P5), OS (P6-P7), or SCID (P8). The 5′ to 3′ orientation of TCRβ V and J genes is shown on the bottom, along with a scale illustrative of the frequency of TRBV-TRBJ gene pairing. ND, Not done. Journal of Allergy and Clinical Immunology 2017 140, 1739-1743.e7DOI: (10.1016/j.jaci.2017.08.001) Copyright © 2017 Terms and Conditions

Fig E3 Suppressive activity of sorted Treg cells from controls and patients with CID/AS (P1 and P4). A, Gating strategy for sorting of Treg and Tconv cells, based on the expression of CD25 and CD127 among CD4+ T cells. Intranuclear FOXP3 staining was performed on a subset of sorted CD25− CD127+ Tconv (gray fill) and of CD25hi CD127lo Treg (black line) cells to confirm their identity. B, Suppression of control Tconv-cell proliferation, as determined by normalization of CellTrace Violet dilution to Tconv cells stimulated in the absence of Treg cells. Shown are the results of suppressive function of Treg cells from controls (black line) or subjects with CID/AS (red line) at the indicated ratios of Tconv:Treg cells to inhibit proliferation of Tconv cells in response to stimulation via CD2/CD3/CD28. Student t test was used for statistical analysis with *P < .05, **P < .01, ***P < .001, and ****P < .0001. In panels A-F, bars represent mean ± SD. Journal of Allergy and Clinical Immunology 2017 140, 1739-1743.e7DOI: (10.1016/j.jaci.2017.08.001) Copyright © 2017 Terms and Conditions