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. 2019 Jul;144(1):333-336.
doi: 10.1016/j.jaci.2019.03.022. Epub 2019 Apr 30.

Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices

Stephen R Daley  1 , Hui-Fern Koay  2 , Kerry Dobbs  3 , Marita Bosticardo  3 , Rushika C Wirasinha  4 , Francesca Pala  3 , Riccardo Castagnoli  3 , Jared H Rowe  5 , Lisa M Ott de Bruin  6 , Sevgi Keles  7 , Yu Nee Lee  8 , Raz Somech  8 , Steven M Holland  3 , Ottavia M Delmonte  3 , Debbie Draper  3 , Sandra Maxwell  3 , Julie Niemela  9 , Jennifer Stoddard  9 , Sergio D Rosenzweig  9 , Pietro Luigi Poliani  10 , Valentina Capo  11 , Anna Villa  12 , Dale I Godfrey  2 , Luigi D Notarangelo  13
Affiliations

Cysteine and hydrophobic residues in CDR3 serve as distinct T-cell self-reactivity indices

Stephen R Daley et al. J Allergy Clin Immunol. 2019 Jul.
No abstract available

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Conflict of interest statement

Disclosure of potential conflict of interest: L. D. Notarangelo is supported by the National Institute of Allergy and Infectious Diseases; has board memberships with the Journal of Clinical Immunology, Clinical Immunology, and Frontiers in Immunology; and has received royalties from UpToDate. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

FIG 1.
FIG 1.
Strong and early TCR activation in type A IELps. A, Phenotypes of sorted human thymocyte subsets. B, Electronically gated subsets (see color code at right) analyzed for Helios expression, with a summary of mean Helios labeling intensity normalized to CD4+CD8+ thymocytes in the same sample. C, Cumulative percentage of unique sequences that used each TRAV or TRAJ segment as a function of chromosomal location in the TRAV (left) or TRAJ (right) locus, with a summary of the area under the curve for each sample (right). D, Trav and Traj use in mouse T-cell subsets analyzed as in Fig 1, C. E-H, Percentage of unique sequences with a self-reactive CDR3 position 6 and 7 doublet (hydrophobic index; see Fig 1, E and F) or percentage of unique sequences with cysteine within 2 positions of the CDR3 apex (cysteine index; Fig 1, G and H; Fig 1, E and G, for human and Fig 1, F and H, for mouse T-cell subsets). Two-way ANOVA was used with repeated measures based on sample donor and TCR chain (α and β), whereas 1-way ANOVA was used to compare TCRβ repertoires. ns, P > .05. Mouse data in Fig 1, H, have been published and are included here to enable comparison with human data.
FIG 2.
FIG 2.
Aberrant self-reactivity indices of T-cell populations selected in the presence of RAG mutations. A and B, Hydrophobic index (Fig 2, A) and cysteine index (Fig 2, B) in CDR3α and CDR3β repertoires of T-cell subsets (x-axis) from healthy control subjects (squares) and patients with RAG mutations (circles). Fifteen samples from patients with RAG mutations were excluded from Fig 2, B, because no sequences were detected with cysteine within 2 positions of the CDR3 apex, and hence the cysteine index was undefined (see Table E2 in this article’s Online Repository at www.jacionline.org). C and D, Hydrophobic index (Fig 2, C) and cysteine index (Fig 2, D) among unique sequences (y-axis) as a function of the same index among total sequences (x-axis). E and F, Hydrophobic index (Fig 2, E) and cysteine index (Fig 2, F) as a function of mean RAG recombination activity. G, Cysteine index (left) and hydrophobic index (right) in unique TCRβ sequences of CD4+ Tconv and Treg cells sorted from B6 control mice or mice with homozygous mutations in Rag2 (R229Q) or Rag1 (R972Q, F971L, or R972W). In Fig 2, A and B, 2-way ANOVA was used to compare healthy control subjects with patients with RAG mutations adjusted with the Sidak multiple comparisons test. **P < .01 and ***P < .001. In Fig 2, C-F, P and ρ values were determined by using the Spearman test for correlation. Horizontal lines in Fig 2, E and F, show the ranges observed in healthy control subjects.
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