Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia

Thumbnail Image

Files

Inborn_errors_of_immunity_underlie_clonal_T_cell_expansions_in_large_granular_lymphocyte_leukemia.pdf (8.46 MB)

Access rights

openAccess
CC BY
publishedVersion

URL

Journal Title

Journal ISSN

Volume Title

A1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä
This publication is imported from Aalto University research portal.
View publication in the Research portal (opens in new window)
View/Open full text file from the Research portal (opens in new window)
Unless otherwise stated, all rights belong to the author. You may download, display and print this publication for Your own personal use. Commercial use is prohibited.

Authors

Date

2025-05-01

Department

Department of Computer Science

Major/Subject

Mcode

Degree programme

Language

en

Pages

18

Series

Journal of Clinical Investigation, Volume 135, issue 9, pp. 1-18

Abstract

BACKGROUND. T cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents a unique model for the study of persistent CTL expansions. Albeit autoimmunity is implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL. METHODS. This is a comprehensive immunogenomic study of 92 consecutive patients from a large T-LGLL cohort with full laboratory-clinical characterization (n = 271). Whole-exome profiling of variants associated with inborn errors of immunity (IEI) and somatic mutations in T cell lymphoid drivers was analyzed. Single-cell RNA-Seq and TCR-Seq in T-LGLL samples and RNA-Seq in T cell cancer cell lines were utilized to establish biological correlations. RESULTS. Lymphocytopenia and/or hypogammaglobulinemia were identified in 186 of 241 (77%) T-LGLL patients. Genetic screening for IEI revealed 43 rare heterozygous variants in 38 different immune genes in 34 of 92 (36%) patients (vs. 167/63,026 [0.26%] in controls). High-confidence deleterious variants associated with dominant, adult-onset IEIs were detected in 15 of 92 (16%) patients. Carriers showed atypical features otherwise tied to the cryptic IEI, such as earlier onset, lower lymphocyte counts, lower STAT3 mutational rate, and higher proportions of hypogammaglobulinemia and immune cytopenia/bone marrow failure than noncarriers. Somatic mutational landscape, RNA-Seq, and TCR-Seq analyses supported immune imbalance caused by the IEI variants and interactions with somatic mutations in T cell lymphoid drivers. CONCLUSIONS. Our findings in T-LGLL reveal that maladaptive CTL expansions may stem from cryptic immunodeficiency traits and open the horizon of IEIs to clonal hematopoiesis and bone marrow failure.

Description

Publisher Copyright: © 2025, Bravo-Perez et al.

Keywords

Other note

DOI

10.1172/JCI184431

Citation

Bravo-Perez, C, Gurnari, C, Huuhtanen, J, Kawashima, N, Guarnera, L, Mandala, A, Williams, N D, Haddad, C, Witt, M, Unlu, S, Brady, Z, Ogbue, O, Orland, M, Ahmed, A, Kubota, Y, Pagliuca, S, Durmaz, A, Mustjoki, S, Visconte, V & Maciejewski, J P 2025, 'Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia', Journal of Clinical Investigation, vol. 135, no. 9, e184431, pp. 1-18. https://doi.org/10.1172/JCI184431

Permanent link to this item

https://urn.fi/URN:NBN:fi:aalto-202505213969

Collections

[article-cris] Perustieteiden korkeakoulu / SCI