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Cells
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Unconventional T Cells in Health and Disease
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Unconventional T Cells in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (28 February 2026) | Viewed by 5648

Special Issue Editor

Dr. Lauren Howson

E-Mail Website
Guest Editor
Immunology Division, Walter & Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
Interests: T cells; MAIT cells; γδ T cells; primary immunodeficiency; infectious diseases

Special Issue Information

Dear Colleagues,

Cutting-edge research over the past 30 years has uncovered a diverse array of unconventional T cells that do not fit neatly into the well-established conventional T cell categories. These include γδ T cells, CD1-restricted T cells, and MR1-restricted T cells, all of which are capable of recognizing non-peptide antigens. These cells sit at the interface of innate and adaptive immunity, allowing them to respond rapidly to a wide range of pathogens, stress signals, tissue damage, and inflammation.

Despite their growing significance, unconventional T cell biology is often considered a niche area of research and is typically divided based on the specific cell type of interest (e.g., MAIT cells, NKT cells, and γδ T cells). However, collectively, this field is transforming our understanding of host immunity. Unconventional T cells are implicated in a wide range of conditions, from infections and autoimmune diseases to cancer and metabolic disorders. However, key aspects of their function, antigen specificity, and therapeutic potential remain elusive.

This Special Issue will bring together the diverse branches of unconventional T cell research to showcase the power and promise of these unique immune cells in improving human immune health. We invite the submission of original research that advances our understanding of any unconventional T cell subset, including their mechanistic roles in health and disease, as well as their potential as novel therapeutic targets. We also welcome reviews that summarize the current state and future directions of unconventional T cell research.

Dr. Lauren Howson
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • MR1-restricted T cells
  • γδ T cells
  • CD1-restricted T cells
  • unconventional T cells

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Published Papers (3 papers)

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Research

23 pages, 9805 KB  
Article
Functional Profile of γδ T Cells in Severe and Moderate COVID-19: A Brazilian Cross-Sectional Study
by Andressa da Silva Cazote, Glenda Domingos Mascarenhas, Hugo Perazzo, Kim Mattos Geraldo, Maria Pia Diniz Ribeiro, Juliana Arruda de Matos, Pedro Emmanuel Alvarenga Americano do Brasil, Sandra Wagner Cardoso, Beatriz Grinsztejn, Valdiléa Gonçalves Veloso, Cynthia Machado Cascabulho, José Henrique Pilotto, Diogo Gama Caetano, Milena Neira Guimarães Goulart, Nathalia Beatriz Ramos de Sá, Dalziza Victalina de Almeida, Fernanda Heloise Côrtes, Mariza Gonçalves Morgado and Carmem Beatriz Wagner Giacoia-Gripp
Cells 2026, 15(11), 1020; https://doi.org/10.3390/cells15111020 - 1 Jun 2026
Viewed by 350
Abstract
This study aimed to identify the distinct intrinsic response potential of γδ T cells from COVID-19 patients with different illness severities, to better understand the implication of these cells in COVID-19 disease. Forty-four COVID patients were enrolled at hospitalization and classified as: moderate [...] Read more.
This study aimed to identify the distinct intrinsic response potential of γδ T cells from COVID-19 patients with different illness severities, to better understand the implication of these cells in COVID-19 disease. Forty-four COVID patients were enrolled at hospitalization and classified as: moderate without oxygen support (MWO2; N = 15), moderate with oxygen support (MO2; N = 15), or severe disease requiring mechanical ventilation (SD; N = 14). γδ T cells were characterized ex vivo, isolated from peripheral blood cells, stimulated in vitro with OKT3 and K562 cells, and evaluated for functional markers by flow cytometry. Ex vivo analysis identified 16.21% of total γδ T cells as Vδ1−Vδ2−. SD patients presented a lower frequency of TRAIL+ and of IL-17-producing Vδ2 cells, as well as lower value of fluorescence intensity values for TNF-α in Vδ2 cells, than MWO2 patients (p < 0.05). In addition, paired analyses showed a lower frequency of IL-17-producing than CD161+ Vδ2 cells in SD patients (p < 0.05). These observations suggest a more restricted response potential of the Vδ2 subset in severe disease, show the impact of general immune dysregulation on these cells, or even suggest some role for IL-17-producing Vδ2 cells in preventing critical symptoms. Full article
(This article belongs to the Special Issue Unconventional T Cells in Health and Disease)
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22 pages, 2395 KB  
Article
Characterization of Stimulated γδ T Cells: Phenotypic Analysis and Implications for Allogeneic Cellular Immunotherapy
by Anna Bold, Heike Gross, Marco Bardenbacher, Elisabeth Holzmann, Stefan Knop and Martin Wilhelm
Cells 2025, 14(23), 1917; https://doi.org/10.3390/cells14231917 - 2 Dec 2025
Cited by 1 | Viewed by 1531
Abstract
Due to their anti-tumor activity and non-major histocompatibility complex (MHC) binding T cell receptor, γδ T cells are suitable candidates for allogeneic cellular immunotherapy in cancer. Recently, we developed a new protocol called Ko-Op for stimulation of γδ T cells (specifically Vy9Vδ2 T [...] Read more.
Due to their anti-tumor activity and non-major histocompatibility complex (MHC) binding T cell receptor, γδ T cells are suitable candidates for allogeneic cellular immunotherapy in cancer. Recently, we developed a new protocol called Ko-Op for stimulation of γδ T cells (specifically Vy9Vδ2 T cells) that generates a cell product consisting mainly of γδ T cells with preserved anti-tumor activity targeted for clinical-grade application. In this study, we investigated the phenotype of stimulated γδ T cells and correlated this with results of functional assays to obtain a deeper understanding of the characteristics of stimulated γδ T cells. Additionally, an intensive analysis of surface molecules of unstimulated and stimulated γδ T cells is presented. Since heterogeneous results regarding the response to therapy with γδ T cells observed in earlier clinical trials could be a consequence of various extents of γδ T cell adhesion and migration ability, we addressed surface molecules associated with cellular activity and adhesion and migration functions as well. By investigating correlations between the phenotype of unstimulated γδ T cells and cellular cytotoxicity, as well as the degranulation ability of stimulated γδ T cells, we could draw conclusions about optimal donors for further allogeneic cellular therapies. Finally, we demonstrated that the phenotype varies over the time of culture and is clearly modifiable by changing the stimulation protocol. Full article
(This article belongs to the Special Issue Unconventional T Cells in Health and Disease)
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14 pages, 516 KB  
Article
The Cytotoxic Potential of Humanized γδ T Cells Against Human Cancer Cell Lines in In Vitro
by Husheem Michael, Abigail T. Lenihan, Mikaela M. Vallas, Gene W. Weng, Jonathan Barber, Wei He, Ellen Chen, Paul Sheiffele and Wei Weng
Cells 2025, 14(15), 1197; https://doi.org/10.3390/cells14151197 - 4 Aug 2025
Viewed by 3163
Abstract
Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to [...] Read more.
Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article
(This article belongs to the Special Issue Unconventional T Cells in Health and Disease)
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