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ORIGINAL RESEARCH article

Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1447625

Azithromycin targets CD27 pathway to modulate CD27hi T-lymphocyte Expansion and Type-1 Effector Phenotype

Provisionally accepted
Abdul W. Ansari Abdul W. Ansari 1Manju N. Jayakumar Manju N. Jayakumar 2Fareed Ahmad Fareed Ahmad 1Thenmozhi Venkatachalam Thenmozhi Venkatachalam 3Laila Salameh Laila Salameh 4Hema Unnikannan Hema Unnikannan 2Thesni Raheed Thesni Raheed 1Abdul Khader Mohammed Abdul Khader Mohammed 2Bassam Mahboub Bassam Mahboub 5Basel K. Al-Ramadi Basel K. Al-Ramadi 6Qutayba Hamid Qutayba Hamid 7Martin Steinhoff Martin Steinhoff 1Rifat Hamoudi Rifat Hamoudi 8*
  • 1 Dermatology Institute, Interim Translational Research Institute, Academic Health Systems, Hamad Medical Corporation, Doha, Qatar
  • 2 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, United Arab Emirates
  • 3 Khalifa University, Abu Dhabi, Abu Dhabi, United Arab Emirates
  • 4 Rashid Hospital, Dubai, United Arab Emirates
  • 5 Department of Pulmonary Medicine, Rashid Hospital, Dubai, United Arab Emirates
  • 6 Department of Medical Microbiology and Immunology, College of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, Abu Dhabi, United Arab Emirates
  • 7 Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates
  • 8 Department of Clinical Science, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates

The final, formatted version of the article will be published soon.

    Macrolide antibiotic azithromycin is widely used in clinical practice to treat respiratory tract infections and inflammatory diseases. However, its mechanism of action is not fully understood.Given the involvement of CD27 pathway in the pathophysiology of various T-lymphocyte mediated inflammatory, autoimmune, and lymphoproliferative diseases, we examined the impact of AZM on CD27 regulation and potential consequences on CD4+ and CD8+ T cell phenotypes.Using cellular immunology approaches on healthy donors' peripheral blood mononuclear cells we demonstrate AZM-mediated downregulation of surface CD27 expression as well as its extracellular release as soluble CD27. Notably, AZM exposed CD27high (hi) cells were defective in their ability to expand compared to CD27intermediate (Int) and CD27low (lo) subsets. The defective CD27hi subset expansion was found to be associated with impaired cell proliferation and cell division. At molecular level, CD27hi subset exhibited lower mTOR activity than other subsets.Functionally, AZM treatment resulted in marked depletion of helper CD4+ (Th1) and cytotoxic CD8+ T-lymphocyte (Tc1) associated CXCR3+CD27hi effector cells, and inhibition of inflammatory cytokine IFN-γ production. These findings provide mechanistic insights on immunomodulatory features of AZM on T-lymphocyte by altering CD27 pathway. From clinical perspective this study also sheds light on potential clinical benefits observed in patients on prophylactic AZM regimens against various respiratory diseases and opens avenues for future adjunct therapy against Th1 and Tc1 dominated inflammatory and autoimmune diseases.

    Keywords: Azithromycin, CD27 subset, T-Lymphocytes, Inflammation, mTOR, Type-1 immunity, CXCR3

    Received: 11 Jun 2024; Accepted: 12 Jul 2024.

    Copyright: © 2024 Ansari, Jayakumar, Ahmad, Venkatachalam, Salameh, Unnikannan, Raheed, Mohammed, Mahboub, Al-Ramadi, Hamid, Steinhoff and Hamoudi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Rifat Hamoudi, Department of Clinical Science, College of Medicine, University of Sharjah, Sharjah, United Arab Emirates

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