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ORIGINAL RESEARCH article

Front. Immunol.

Sec. Immunological Tolerance and Regulation

Human tolerogenic dendritic cell subtypes exert divergent effects on induction of cytotoxic CD4+ T cells

Provisionally accepted
Gabrielle BarranGabrielle Barran1,2Najib NamaaneNajib Namaane1Abdul Mannan BaruAbdul Mannan Baru3Amy Elizabeth AndersonAmy Elizabeth Anderson1Jane FalconerJane Falconer2Catharien Maria Ursula HilkensCatharien Maria Ursula Hilkens1*
  • 1Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom
  • 2John Dawson Drug Discovery and Development Institute, University of Sunderland, Sunderland, United Kingdom
  • 3Immunology Network, Immunology Research Unit, GlaxoSmithKline, Stevenage, United Kingdom

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Tolerogenic dendritic cells (tolDC) are currently in clinical trials for the treatment of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis. The methods for producing therapeutic tolDC vary widely, with little being known about the commonalities and differences of distinct cell products in terms of their regulatory actions on CD4+ T cells. We compared human monocyte-derived tolDC generated with vitamin D3 alone or in combination with dexamethasone. We found marked differences in the surface expression of HLA-DR and immune regulatory molecules, but also found commonalities, e.g. a strongly reduced capacity to produce interleukin-12 and a concomitant decreased ability to induce interferon-g secretion by allogeneic CD4+ T cells. To gain a deeper understanding of how these tolDC types exert their regulatory effects, we co-cultured them with CD4+ T cells from rheumatoid arthritis patients or healthy controls and analysed the gene expression profile and function of the responding T cells. We found that tolDC generated with vitamin D3 alone, but not in combination with dexamethasone, induced potent cytotoxic activity in the responding CD4+ T cells as demonstrated by an enhanced cytotoxic gene signature, increased levels of intracellular granzyme B, and superior cytotoxic activity towards myeloid and B cells. These data identify cytotoxicity as an atypical CD4+ T helper cell effector function induced by some but not all tolDC types, with implications for their individual clinical applications.

Keywords: Autoimmune Diseases, cytotoxic CD4+ T cells, Dexamethasone, Rheumatoidarthritis, Tolerogenic dendritic cells, Vitamin D3

Received: 03 Sep 2025; Accepted: 27 Nov 2025.

Copyright: © 2025 Barran, Namaane, Baru, Anderson, Falconer and Hilkens. 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: Catharien Maria Ursula Hilkens

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Supplementary Material