Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia
Carlos Bravo-Perez, … , Valeria Visconte, Jaroslaw P. Maciejewski
Carlos Bravo-Perez, … , Valeria Visconte, Jaroslaw P. Maciejewski
Published May 1, 2025
Citation Information: J Clin Invest. 2025;135(9):e184431. https://doi.org/10.1172/JCI184431.
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Clinical Research and Public Health Genetics Hematology

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

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.FUNDING NIH; Aplastic Anemia and MDS International Foundation; VeloSano; Edward P. Evans Foundation; Instituto de Salud Carlos III; European Research Council; European Research Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.

Authors

Carlos Bravo-Perez, Carmelo Gurnari, Jani Huuhtanen, Naomi Kawashima, Luca Guarnera, Aashray Mandala, Nakisha D. Williams, Christopher Haddad, Michaela Witt, Serhan Unlu, Zachary Brady, Olisaemeka Ogbue, Mark Orland, Arooj Ahmed, Yasuo Kubota, Simona Pagliuca, Arda Durmaz, Satu Mustjoki, Valeria Visconte, Jaroslaw P. Maciejewski

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Figure 6

TCR repertoire analyses of the implications of the hcD variants associated with dominant IEI.

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TCR repertoire analyses of the implications of the hcD variants associat...
(A) Patient flow for TCR immunosequencing. Of 20 T-LGLL patients with WES and deep TCR sequencing, 18 patients were downstream analyzed after resampling to 5,420 clones. Data from 145 healthy controls from Pagliuca et al. were also used (45). (B) Pooled distribution of clones according to the expansion status. Nonexpanded, normally expanded, and pathologically expanded clonotypes are defined by 1, 2–5, and >5 templates, respectively. (C) Number of unique, normally expanded, and pathologically expanded clonotypes, inverse Simpson index, and mean clone size between T-LGLL versus healthy controls and between hcD carriers and noncarriers (NC) within the T-LGLL cases. One dot per sample. Mann-Whitney U test P values are shown. (D) Bar plot illustrating the condition-related known specificities of the whole repertoire (upper plot) and only the pathologically expanded clonotypes (lower plot) in healthy controls and T-LGLL patients with/without hcD variants. (E) Proposed model on the pathogenic role of underlying IEI in CTL proliferations and clonal shift (created with Biorender.com). Aberrant immune responses caused by genetic or acquired factors, both deficient or hyperreactive abnormal responses, may lead to antigen persistence and/or immune dysregulation and eventually result in T-LGLL as a pathologic overcompensation. *P < 0.05; **P < 0.01; ***P < 0.001. Ag: antigen; CMV, cytomegalovirus; IBD, inflammatory bowel disease; HPV, human papillomavirus; NOS, not otherwise specified; sIg, surface Ig; SLE, systemic lupus erythematosus; VZV, varicella zoster virus.