T-cell receptor diversity is selectively skewed in T-cell populations of patients with Wiskott-Aldrich syndrome Junfeng Wu, MD, Dawei Liu, MS, Wenwei.

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Presentation transcript:

T-cell receptor diversity is selectively skewed in T-cell populations of patients with Wiskott-Aldrich syndrome Junfeng Wu, MD, Dawei Liu, MS, Wenwei Tu, MD, PhD, Wenxia Song, PhD, Xiaodong Zhao, MD, PhD Journal of Allergy and Clinical Immunology Volume 135, Issue 1, Pages 209-216.e8 (January 2015) DOI: 10.1016/j.jaci.2014.06.025 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Analysis of T-cell repertoires in sorted CD4+ and CD8+ T cells. A, CDR3 size distribution of TCR Vβ subfamilies. The CDR3 size distribution in sorted CD4+ and CD8+ T cells from a patient with WAS (P8) is shown. B, Complexity scores of TCR Vβ. The complexity scores of CD4+ and CD8+ T cells for each healthy control subject and patient are shown (top). The mean (with range) complexity scores for CD4+ and CD8+ T cells are shown in the histogram (bottom). HC, Healthy control subjects; P, patients. ***P < .0001. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Analysis of T-cell repertoires in sorted CD45RA+CD4+, CD45RA+CD8+, CD45RO+CD4+, and CD45RO+CD8+ T cells. A, CDR3 size distribution of TCR Vβ subfamilies. CDR3 size distributions in CD4+CD45RA+ (4RA), CD4+CD45RO+ (4RO), CD8+CD45RA+ (8RA), and CD8+CD45RO+ (8RO) T cells from a control donor and from a patient with WAS (P15) are shown. B, Complexity scores of TCR Vβ. The complexity scores of CD45RA+CD4+, CD45RA+CD8+, CD45RO+CD4+, and CD45RO+CD8+ T cells for each healthy control subject and patient are shown (top). The mean (with range) complexity scores are shown in the histograms below. HC, Healthy control subjects; P, patients. *P < .05 and ** P < .01. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Frequency of skewed TCR Vβ repertoires. Shown are the median (with range) frequencies of skewed TCR Vβ subfamilies in total peripheral T cells (A), CD4+ and CD8+ T cells (B), and CD45RA+CD4+, CD45RA+CD8+, CD45RO+CD4+, and CD45RO+CD8+ T cells (C) from the control and patient groups. HC, Healthy control subjects; P, patient; 4RA, CD4+CD45RA+ T cells; 8RA, CD8+CD45RA+ T cells; 4RO, CD4+CD45RO+ T cells; 8RO, CD8+CD45RO+ T cells. *P < .05 and ** P < .01. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 HTS for TCR diversity analysis. TCR diversity was measured by using H′, which is a reflection of the change in richness (A), and Ds, which is a reflection of the change in evenness (B), in the indicated groups. Symbols represent individual subjects, and bars depict group means. *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Purity of sorted cell populations. CD4+ and CD8+ T cells (CD3+, left-hand dot plot) were gated and sorted by expression of CD45RA or CD45RO to purify naive (green) and memory (blue) subsets in A, respectively. Expression of CD45RO or CCR7 was used to purify the CD8+ Temra cells (blue dots in B and gray dots in C) and naive CD8+ T-cell (orange dots in B) subsets, respectively. Three representative patients are shown. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Analysis of T-cell repertoires in total peripheral T cells. A, CDR3 size distribution of TCR Vβ subfamilies. The CDR3 size distribution in total peripheral T cells from a control subject and a patient with WAS (P5) are shown. B, TCR Vβ complexity scores. The complexity scores for each healthy control subject (left) and patient (middle) are shown. The mean (with range) complexity scores of the patient and control groups are shown in the histogram (right). HC, Healthy control subjects; P, patients. **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 HTS of TCR diversity analysis. TCR diversity was measured based on the D50 value of clonotypes (A) and the D50 value of CDR3 amino acid sequences (B) in the indicated group. HC, Healthy control subjects; n = 7/6δ, n = 7 in 8Temra cells but n = 6 in 8 naive cells; 8Naive, naive CD8+ T cells (CD8+CD45RO−CCR7+); P, patients; 4RA, CD4+CD45RA+ T cells; 8RA, CD8+CD45RA+ T cells; 4RO, CD4+CD45RO+ T cells; 8RO, CD8+CD45RO+ T cells; 8Temra, CD8+ terminally differentiated effector memory T cells (CD8+CD45RO−CCR7−). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Analysis of V, D, and J gene use in the analyzed cohorts by using HTS. A, Vβ gene use of TCRs in different T-cell subsets from 25 healthy control subjects and 15 patients with WAS. The 15 most frequent Vβ genes are indicated in color, and the remaining 33 Vβ genes are grouped together in dark green. B and C, Dβ (Fig E4, B) and Jβ (Fig E4, C) gene use of TCRs in different T-cell subsets from patients with WAS and healthy control subjects. HC, Healthy control subjects; P, patients; 4RA, CD4+CD45RA+ T cells; 8RA, CD8+CD45RA+ T cells; 4RO, CD4+CD45RO+ T cells; 8Naive, CD8+CD45RO−CCR7+ T cells; 8Temra, CD8+CD45RO−CCR7− T cells. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Expansion of public CDR3 amino acid sequences in healthy control subjects and patients with WAS. The Venn diagrams present the total number of CDR3 amino acid sequences that were shared between healthy control subjects (red) and patients (green) for a given T-cell subset (A-E) or between different T-cell subsets within the same donor population (patients or control subjects; F and G: red, 4RO; green, 8RA; and blue, 4RA; H and I: red, 8Naive; and green, 8Temra). Numbers of CDR3 sequences that are unique to each subset are shown in the nonoverlapping sections. Numbers of CDR3 sequences that are common to any 2 and 3 of these subsets are indicated in the relevant overlapping areas. HC, Healthy control subjects; 8Naive, CD8+CD45RO−CCR7+ T cells; P, patients; 4RA, CD4+CD45RA+ T cells; 8RA, CD8+CD45RA+ T cells; 4RO, CD4+CD45RO+ T cells; 8Temra, CD8+CD45RO−CCR7− T cells. Journal of Allergy and Clinical Immunology 2015 135, 209-216.e8DOI: (10.1016/j.jaci.2014.06.025) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions