Frontiers in Immunology (Oct 2024)

Activating STAT3 mutations in CD8+ T-cells correlate to serological positivity in rheumatoid arthritis

  • Katharine B. Moosic,
  • Katharine B. Moosic,
  • Katharine B. Moosic,
  • Thomas L. Olson,
  • Thomas L. Olson,
  • Mark Freijat,
  • Samara Khalique,
  • Cait E. Hamele,
  • Cait E. Hamele,
  • Bryna Shemo,
  • Bryna Shemo,
  • Jesse Boodoo,
  • William Baker,
  • Gitanjali Khurana,
  • Matthew Schmachtenberg,
  • Matthew Schmachtenberg,
  • Tristin Duffy,
  • Tristin Duffy,
  • Aakrosh Ratan,
  • Aakrosh Ratan,
  • Aakrosh Ratan,
  • Erika Darrah,
  • Felipe Andrade,
  • Marieke Jones,
  • Kristine C. Olson,
  • Kristine C. Olson,
  • David J. Feith,
  • David J. Feith,
  • Donald L. Kimpel,
  • Thomas P. Loughran,
  • Thomas P. Loughran

DOI
https://doi.org/10.3389/fimmu.2024.1466276
Journal volume & issue
Vol. 15

Abstract

Read online

ObjectivesLarge granular lymphocyte (LGL) leukemia is a rare hematologic malignancy characterized by clonal expansion of cytotoxic T-cells frequent somatic activating STAT3 mutations. Based on the disease overlap between LGL leukemia rheumatoid arthritis (RA)a putative role for CD8+ T-cells in RA we hypothesized that STAT3 mutations may be detected in RA patient CD8+ T-cells correlate with clinical characteristics.MethodsBlood samples, clinical parameters, and demographics were collected from 98 RA patients and 9 healthy controls (HCs). CD8+ cell DNA was isolated and analyzed via droplet digital (dd)PCR to detect STAT3 mutations common in LGL leukemia: Y640F, D661Y, and the S614 to G618 region. STAT3 data from 99 HCs from a public dataset supplemented our 9 HCs.ResultsRA patients had significantly increased presence of STAT3 mutations compared to controls (Y640F p=0.0005, D661Y p=0.0005). The majority of these were low variant allele frequency (VAF) (0.008-0.05%) mutations detected in a higher proportion of the RA population (31/98 Y640F, 17/98 D661Y) vs. HCs (0/108 Y640F, 0/108 D661Y). In addition, 3/98 RA patients had a STAT3 mutation at a VAF >5% compared to 0/108 controls. Serological markers, RF and anti-CCP positivity, were more frequently positive in RA patients with STAT3 mutation relative to those without (88% vs 59% RF, p=0.047; 92% vs 58% anti-CCP, p=0.031, respectively).ConclusionsSTAT3 activating mutations were detected in RA patient CD8+ cells and associated with seropositivity. Thus, STAT3 activating mutations may play a role in disease pathogenesis in a subset of RA patients.

Keywords