FOXP3+ regulatory T cells are associated with the severity and prognosis of sarcoidosis

Karen C Patterson; Wallace T Miller; Wayne W Hancock; Tatiana Akimova

doi:10.3389/fimmu.2023.1301991

FOXP3+ regulatory T cells are associated with the severity and prognosis of sarcoidosis

Front Immunol. 2023 Dec 20:14:1301991. doi: 10.3389/fimmu.2023.1301991. eCollection 2023.

Authors

Karen C Patterson¹, Wallace T Miller², Wayne W Hancock³, Tatiana Akimova³

Affiliations

¹ Division of Pulmonary, Allergy, and Critical Care Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
² Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
³ Division of Transplant Immunology, Department of Pathology and Laboratory Medicine, and Biesecker Center for Pediatric Liver Diseases, Children's Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

Abstract

Rationale: Sarcoidosis is an inflammatory granulomatous disease of unknown etiology with predominant lung involvement. Organ involvement and disease severity, as well as the nature of immune alterations, vary among patients leading to a range of clinical phenotypes and outcomes. Our objective was to evaluate the association of disease course and immune responses in pulmonary sarcoidosis.

Methods: In this prospective cohort study of 30 subjects, most of whom were followed for one year, we evaluated 14 inflammatory markers in plasma, 13 Treg/T cell flow cytometry markers and 8 parameters of FOXP3⁺ Treg biology, including suppressive function, epigenetic features and stability.

Results: We identified a set of 13 immunological parameters that differ in sarcoidosis subjects in comparison with healthy donors. Five of those were inversely correlated with suppressive function of Tregs in sarcoidosis, and six (TNFα, TNFR I and II, sCD25, Ki-67 and number of Tregs) were particularly upregulated or increased in subjects with thoracic lymphadenopathy. Treg suppressive function was significantly lower in patients with thoracic lymphadenopathy, and in patients with higher burdens of pulmonary and systemic symptoms. A combination of five inflammatory markers, Ki-67 expression, Treg function, and lung diffusion capacity evaluated at study entry predicted need for therapy at one year follow-up in 90% of cases.

Conclusion: Tregs may suppress ongoing inflammation at local and systemic levels, and TNFα, TNFR I and II, sCD25 and Ki-67 emerge as attractive biomarkers for in vivo sarcoid inflammatory activity.

Keywords: Ki-67; TNFRI; TNFRII; TNFα; Treg; regulatory T-cells; sCD25; sarcoidosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Forkhead Transcription Factors / metabolism
Humans
Ki-67 Antigen / metabolism
Lymphadenopathy*
Prognosis
Prospective Studies
Receptors, Tumor Necrosis Factor, Type I / metabolism
Sarcoidosis* / metabolism
T-Lymphocytes, Regulatory
Tumor Necrosis Factor-alpha / metabolism

Substances

Receptors, Tumor Necrosis Factor, Type I
Tumor Necrosis Factor-alpha
Ki-67 Antigen
Forkhead Transcription Factors
FOXP3 protein, human

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work was supported by an Institute for Translational Medicine and Therapeutics, Junior Investigator Preliminary/Feasibility Grant Program (JIPGP) Award, University of Pennsylvania (KP).