Antiviral immune response against HTLV-1 invalidates T-SPOT.TB® results in patients with HTLV-1-positive rheumatic diseases

Front Immunol. 2024 Oct 29:15:1480506. doi: 10.3389/fimmu.2024.1480506. eCollection 2024.

Abstract

Background: T-SPOT.TB®, one of the screening tests for latent tuberculosis infection (LTBI), yields invalid results in human T-cell leukemia virus type 1 (HTLV-1)-positive patients with rheumatoid arthritis. However, the detailed mechanisms behind this invalidation are unclear. Additionally, it remains unclear whether T-SPOT.TB® or QuantiFERON-TB (QFT) is more useful in HTLV-1-positive patients with rheumatic disease (RD).

Method: Among all of the HTLV-1-positive RD patients who visited our department between August 2012 and December 2022, 44 patients who were screened using T-SPOT.TB® were included in the analysis. QFT testing was performed in 33 of the 44 patients, and the results were compared with that of T-SPOT.TB®. Furthermore, we performed a culture experiment mimicking T-SPOT.TB® using peripheral blood mononuclear cells (PBMCs) obtained from HTLV-1-positive patients with RD. Additionally, T-cell subsets with autonomous product IFN-γ were analyzed using a flow cytometer.

Results: Of the included patients, 13 (29.5%) were invalid for T-SPOT.TB® because of the increased number of negative control spots. The median HTLV-1 proviral load in the invalid group was higher than that in the valid group (2.45 vs. 0.49 copies/100 PBMCs, respectively, p = 0.002). QFT was performed in all 33 patients, including 13 patients who were invalid in T-SPOT.TB®. The main source of IFN-γ production was CD8+ T-cells in the T-SPOT.TB® mimic experiment. Furthermore, Tax-expressing CD4+ T-cells and Tax-specific cytotoxic CD8+ T-cells were more frequently observed in patients with invalid results than in patients with valid results. CD4+ T-cell depletion in the T-SPOT.TB® mimic experiment reduced the population of IFN-γ producing CD8+ T cells.

Conclusion: T-SPOT.TB® may be invalidated by the interaction between Tax-expressing CD4+ T-cells and cytotoxic CD8+ T-cells. Moreover, HTLV-1-associated immune reactions due to contact between these cells may be unlikely to occur in QFT using whole blood. Therefore, our results reveal the superiority of QFT over T-SPOT.TB® as a screening test for LTBI in HTLV-1-positive patients with RD.

Keywords: HTLV-1; IFN-γ-releasing assay; cytotoxic T lymphocytes; latent tuberculosis infection; rheumatic disease.

MeSH terms

  • Adult
  • Aged
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Female
  • HTLV-I Infections* / immunology
  • Human T-lymphotropic virus 1* / immunology
  • Humans
  • Interferon-gamma Release Tests
  • Interferon-gamma* / immunology
  • Latent Tuberculosis / diagnosis
  • Latent Tuberculosis / immunology
  • Leukocytes, Mononuclear / immunology
  • Male
  • Middle Aged
  • Rheumatic Diseases* / immunology

Substances

  • Interferon-gamma

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This study was supported by a grant from the Practical Research Project for Rare/Intractable Diseases of the Japan Agency for Medical Research and Development (Grant No. 20ek0109356h0003, 23ek0109529h0003), Grants-in-Aid for Scientific Research (C) [KAKENHI] (Grant No. 20K08776) and a Grant-in-Aid for Clinical Research from Miyazaki University Hospital.