CD4+ tissue-resident memory T cells and their role in immunity Margarida Kirkby, Marc Veldhoen Immunology and Cell Biology, 2025 CD4+ tissue‐resident memory T (TRM) cells are essential for immune protection in the lungs, providing rapid responses against respiratory pathogens. Unlike circulating memory T cells, CD4+ TRM cells persist in the tissue parenchyma and possibly inducible lymphoid tissues, where they facilitate pathogen clearance through cytokine production and interactions with local immune cells. While CD8+ TRM cells are well studied, the role of CD4+ TRM cells in immunity remains less defined and is the focus of this review. Distinct subsets, based on the effector TH1, TH2, TH17 and T follicular helper (TFH)‐like tissue‐resident helper (TRH) cells, contribute to antiviral, antibacterial, antifungal and vaccine‐induced immunity. CD4+ TRM cells play a key role in infections, enhancing immune responses and supporting antibody production. However, they are also implicated in chronic inflammation, allergies and fibrosis. Given their importance, vaccines aiming to elicit lung‐resident CD4+ TRM cells, particularly via mucosal delivery, have shown promise in inducing long‐term protective immunity. Intranasal vaccination strategies, such as live‐attenuated influenza virus and tuberculosis vaccines, have successfully generated CD4+ TRM cells, highlighting their potential for respiratory pathogen control. In this review, we focus on CD4+ TRM cells, their differentiation, maintenance and role, especially in the lungs.
Metabolic Stress Expands Polyfunctional, Proinflammatory Th17 Cells in Patients With Psoriatic Arthritis for Whom There is Interleukin-23–Independent Interleukin-17 Production Carmel B. Stober, Louise Ellis, Jane C. Goodall, Marc Veldhoen, J. S. Hill Gaston Arthritis and Rheumatology, 2025 ObjectiveGenetic associations and blockade of the interleukin (IL)‐23/IL‐17 axis with monoclonal antibodies support a role for this pathway in patients with psoriatic arthritis (PsA). This study examines the requirement of IL‐23 for IL‐17 production and the role of the metabolic microenvironment in the expansion of Th17‐derived cells in patients with PsA.MethodsTh17 cell frequencies in synovial fluid or peripheral blood from patients with PsA were evaluated by flow cytometry using chemokine receptor 6, CD161, and T‐bet as phenotypic markers, and the cytokines interferon γ, granulocyte–macrophage colony‐stimulating factor (GM‐CSF), and IL‐17 were assessed by flow cytometry and enzyme‐linked immunosorbent assay. The impact of IL‐23 and metabolic stress on T cell differentiation was investigated.ResultsPolyfunctional positive IL‐17 (IL‐17pos) CD4 (P < 0.0001) and CD8 (P < 0.0001), and GM‐CSFpos Th17‐derived cells (P < 0.0001) were increased in the inflamed joints of patients with PsA, with a proportional decrease in the peripheral blood of patients. We demonstrate IL‐23–independent IL‐17 release by CD4 T cells in patients with PsA, in which the absence of IL‐23 during Th17 differentiation reduced IL‐17 by mean ± SEM 31% ± 5.8%. Exogenous IL‐23 increased IL‐17, negatively regulated GM‐CSF, and cooperated with transforming growth factor β to augment IL‐17. Polyfunctional Th17 and Th17‐derived cells, but not Th1 cells, were expanded by metabolic stress in patients with PsA.ConclusionWe confirmed the abundance of polyfunctional type 17 CD4 and CD8 cells in the inflamed joints of patients with PsA. We demonstrate IL‐23–independent expansion of Th17 cells, for which IL‐23 negatively regulates GM‐CSF. This may account for therapeutic differences in IL‐17 and IL‐23 inhibition in patients with PsA or other spondyloarthritides. Polyfunctional IL‐17pos Th17 and Th17‐derived but not Th1 cells were expanded by metabolic stress, and metabolic stress may itself represent a unique therapeutic target.
Systems biology to unravel Western diet-associated triggers in inflammatory bowel disease Špela Konjar, Evgen Benedik, Marko Šestan, Marc Veldhoen, Anže Županič Frontiers in Immunology, 2025 The global rise in inflammatory bowel disease (IBD) and other non-communicable diseases (NCDs) over the past five decades has coincided with the widespread adoption of a Western diet and lifestyle. These conditions, characterised by chronic inflammation, are shaped by complex interactions between genetic, environmental, immunological, and microbial factors. The Western diet rich in, refined sugars, unhealthy fats, ultra-processed foods and excess salt, is increasingly recognised as a major contributor to immune dysfunction, microbial dysbiosis, and compromised intestinal barrier integrity, all hallmarks of IBD. Systems biology offers a powerful framework for untangling the complexity of IBD by integrating large-scale biological data from various sources, leveraging computational modelling, high-throughput analyses, and network-based approaches to identify key regulatory pathways and molecular interactions driving disease progression. Complementary to this, nutritional epidemiology provides critical insights into the role of diet in IBD pathogenesis. By combining systems biology with nutritional epidemiology, researchers can move toward personalised dietary interventions and new therapeutic strategies, offering new opportunities for prevention and addressing the growing burden of IBD in societies adopting Western lifestyles. This review synthesise current findings and proposes integrated approaches for future precision prevention and treatment of IBD.
Tissue-resident memory T cells: Harnessing their properties against infection for cancer treatment João Fernandes, Marc Veldhoen, Cristina Ferreira Bioessays, 2024 We have rapidly gained insights into the presence and function of T lymphocytes in non‐lymphoid tissues, the tissue‐resident memory T (TRM) cells. The central pillar of adaptive immunity has been expanded from classic central memory T cells giving rise to progeny upon reinfection and effector memory cells circulating through the blood and patrolling the tissues to include TRM cells that reside and migrate inside solid organs and tissues. Their development and maintenance have been studied in detail, providing exciting clues on how their unique properties used to fight infections may benefit therapies against solid tumors. We provide an overview of CD8 TRM cells and the properties that make them of interest for vaccination and cancer therapies.
CD8+ tissue-resident memory T-cell development depends on infection-matching regulatory T-cell types Leandro Barros, Daryna Piontkivska, Patrícia Figueiredo-Campos, Júlia Fanczal, Sofia Pereira Ribeiro, et al. Nature Communications, 2023 Immunological memory is critical for immune protection, particularly at epithelial sites, which are under constant risk of pathogen invasions. To counter invading pathogens, CD8+ memory T cells develop at the location of infection: tissue-resident memory T cells (TRM). CD8+ T-cell responses are associated with type-1 infections and type-1 regulatory T cells (TREG) are important for CD8+ T-cell development, however, if CD8+ TRM cells develop under other infection types and require immune type-specific TREG cells is unknown. We used three distinct lung infection models, to show that type-2 helminth infection does not establish CD8+ TRM cells. Intracellular (type-1) and extracellular (type-3) infections do and rely on the recruitment of response type-matching TREG population contributing transforming growth factor-β. Nevertheless, type-1 TREG cells remain the most important population for TRM cell development. Once established, TRM cells maintain their immune type profile. These results may have implications in the development of vaccines inducing CD8+ TRM cells.
Humoral and T cell responses to SARS-CoV-2 reveal insights into immunity during the early pandemic period in Pakistan Kiran Iqbal Masood, Shama Qaiser, Syed Hani Abidi, Erum Khan, Syed Faisal Mahmood, et al. BMC Infectious Diseases, 2023 Background Protection against SARS-CoV-2 is mediated by humoral and T cell responses. Pakistan faced relatively low morbidity and mortality from COVID-19 through the pandemic. To examine the role of prior immunity in the population, we studied IgG antibody response levels, virus neutralizing activity and T cell reactivity to Spike protein in a healthy control group (HG) as compared with COVID-19 cases and individuals from the pre-pandemic period (PP). Methods HG and COVID-19 participants were recruited between October 2020 and May 2021. Pre-pandemic sera was collected before 2018. IgG antibodies against Spike and its Receptor Binding Domain (RBD) were determined by ELISA. Virus neutralization activity was determined using a PCR-based micro-neutralization assay. T cell – IFN-γ activation was assessed by ELISpot. Results Overall, the magnitude of anti-Spike IgG antibody levels as well as seropositivity was greatest in COVID-19 cases (90%) as compared with HG (39.8%) and PP (12.2%). During the study period, Pakistan experienced three COVID-19 waves. We observed that IgG seropositivity to Spike in HG increased from 10.3 to 83.5% during the study, whilst seropositivity to RBD increased from 7.5 to 33.3%. IgG antibodies to Spike and RBD were correlated positively in all three study groups. Virus neutralizing activity was identified in sera of COVID-19, HG and PP. Spike reactive T cells were present in COVID-19, HG and PP groups. Individuals with reactive T cells included those with and without IgG antibodies to Spike. Conclusions Antibody and T cell responses to Spike protein in individuals from the pre-pandemic period suggest prior immunity against SARS-CoV-2, most likely from cross-reactive responses. The rising seroprevalence observed in healthy individuals through the pandemic without known COVID-19 may be due to the activation of adaptive immunity from cross-reactive memory B and T cells. This may explain the more favourable COVID-19 outcomes observed in this population.
Host cell traversal by Plasmodium parasites is essential for sterilizing hepatic cellular immunity A Rodrigues, AM Mendes, R Gonçalves, H Nunes-Cabaço, S Marques, ... bioRxiv, 2026.03. 20.713177 , 2026 2026
YME1L1 is Dispensable for T Lymphocyte Activation Despite its Upregulation and Activity G Malpica, M Joaquim, RS Machado, J Fernandes, MJ Hall, G Martins, ... bioRxiv, 2026.03. 16.712079 , 2026 2026
Systems Biology to Unravel Western Diet-Associated Triggers in Inflammatory Bowel Disease Š Konjar, E Benedik, M Šestan, M Veldhoen, A Zupanic Frontiers in Immunology 16, 1621334 , 2025 2025 Citations: 8
CD4 + tissue‐resident memory T cells and their role in immunity M Kirkby, M Veldhoen Immunology and Cell Biology 103 (8), 809-819 , 2025 2025 Citations: 7
T Cells CDACV FERREIRA, M VELDHOEN US Patent App. 17/999,087 , 2025 2025
Lessons from Portugal on effects of cutting research funding M Veldhoen, JT Barata, LM Figueiredo, CM Azzalin Nature 639 (8056), 867-867 , 2025 2025 Citations: 1
Pre-existing IgG antibodies to HCoVs NL63 and OC43 Spike increased during the pandemic and after COVID-19 vaccination Z Hasan, KI Masood, M Veldhoen, S Qaiser, M Alenquer, M Akhtar, ... Heliyon 11 (3) , 2025 2025 Citations: 7
Metabolic Stress Expands Polyfunctional, Proinflammatory Th 17 Cells in Patients With Psoriatic Arthritis for Whom There is Interleukin‐23–Independent Interleukin … CB Stober, L Ellis, JC Goodall, M Veldhoen, JSH Gaston Arthritis & Rheumatology , 2025 2025 Citations: 3
IgG antibodies to SARS-CoV-2 in asymptomatic blood donors at two time points in Karachi (vol 17, e0271259, 2022) M Hasan, B Moiz, S Qaiser, KI Masood, Z Ghous, A Hussain, N Ali, ... PLOS ONE 19 (12) , 2024 2024
Finding Their Place: Maintenance of Tissue Resident Memory T Cells in Lung Infections JC Lone, G Malpica, L Dratva, C Ferreira, L Barros, RA Vieira, C Mendes, ... EUROPEAN JOURNAL OF IMMUNOLOGY 54, 1335-1335 , 2024 2024
A role for a novel factor in T cell biology G Malpica, S Ariotti, H Mukhopadhyay, G Vicente, A Radcke, M Veldhoen EUROPEAN JOURNAL OF IMMUNOLOGY 54, 1495-1495 , 2024 2024
Tissue-resident memory T cells: Harnessing their properties against infection for cancer treatment J Fernandes, M Veldhoen, C Ferreira BioEssays: news and reviews in molecular, cellular and developmental biology … , 2024 2024 Citations: 1
Metabolic Stress expands Polyfunctional, Proinflammatory Th17 cells in Psoriatic Arthritis, where there is IL-23-independent IL-17 production CB Stober, L Ellis, JC Goodall, M Veldhoen, JSH Gaston Arthritis Rheumatol 10 , 2024 2024
Humoral and T cell responses to SARS-CoV-2 reveal insights into immunity during the early pandemic period in Pakistan KI Masood, S Qaiser, SH Abidi, E Khan, SF Mahmood, A Hussain, ... BMC Infectious Diseases 23 (1), 846 , 2023 2023 Citations: 14
De novo human angiotensin-converting enzyme 2 decoy NL-CVX1 protects mice from severe disease after severe acute respiratory syndrome coronavirus 2 infection M Rebelo, C Tang, AR Coelho, C Labão-Almeida, MM Schneider, ... The Journal of infectious diseases 228 (6), 723-733 , 2023 2023 Citations: 5
CD8 + tissue-resident memory T-cell development depends on infection-matching regulatory T-cell types L Barros, D Piontkivska, P Figueiredo-Campos, J Fanczal, SP Ribeiro, ... Nature Communications 14 (1), 5579 , 2023 2023 Citations: 26
Investigating the impact of prior COVID‐19 on IgG antibody and interferon γ responses after BBIBP‐CorV vaccination in a disease endemic population: A prospective observational … Z Hasan, KI Masood, S Qaiser, E Khan, A Hussain, Z Ghous, U Khan, ... Health Science Reports 6 (9), e1521 , 2023 2023 Citations: 10
SARS‐CoV‐2 clearance after breakthrough infection correlates with fit and happy T cells M Veldhoen, A Bertoletti Immunology and Cell Biology 101 (7), 587-589 , 2023 2023 Citations: 3
IgG antibodies to SARS-CoV-2 in asymptomatic blood donors at two time points in Karachi M Hasan, B Moiz, S Qaiser, KI Masood, Z Ghous, A Hussain, N Ali, ... PloS one 17 (8), e0271259 , 2022 2022 Citations: 18
MOST CITED SCHOLAR PUBLICATIONS
TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells M Veldhoen, RJ Hocking, CJ Atkins, RM Locksley, B Stockinger Immunity 24 (2), 179-189 , 2006 2006 Citations: 5261
The aryl hydrocarbon receptor links TH 17-cell-mediated autoimmunity to environmental toxins M Veldhoen, K Hirota, AM Westendorf, J Buer, L Dumoutier, JC Renauld, ... Nature 453 (7191), 106-109 , 2008 2008 Citations: 2091
Transforming growth factor-β'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9–producing subset M Veldhoen, C Uyttenhove, J Van Snick, H Helmby, A Westendorf, J Buer, ... Nature immunology 9 (12), 1341-1346 , 2008 2008 Citations: 1864
Fate mapping of IL-17-producing T cells in inflammatory responses K Hirota, JH Duarte, M Veldhoen, E Hornsby, Y Li, DJ Cua, H Ahlfors, ... Nature immunology 12 (3), 255-263 , 2011 2011 Citations: 1497
Guidelines for the use of flow cytometry and cell sorting in immunological studies A Cossarizza, HD Chang, A Radbruch, M Akdis, I Andrä, F Annunziato, ... European journal of immunology 47 (10), 1584-1797 , 2017 2017 Citations: 1300
Guidelines for the use of flow cytometry and cell sorting in immunological studies A Cossarizza, HD Chang, A Radbruch, A Acs, D Adam, S Adam‐Klages, ... European journal of immunology 49 (10), 1457-1973 , 2019 2019 Citations: 1211
Interleukin-17-producing γδ T cells selectively expand in response to pathogen products and environmental signals B Martin, K Hirota, DJ Cua, B Stockinger, M Veldhoen Immunity 31 (2), 321-330 , 2009 2009 Citations: 1093
Differentiation and function of Th17 T cells B Stockinger, M Veldhoen Current opinion in immunology 19 (3), 281-286 , 2007 2007 Citations: 1080
Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation Y Li, S Innocentin, DR Withers, NA Roberts, AR Gallagher, EF Grigorieva, ... Cell 147 (3), 629-640 , 2011 2011 Citations: 970
Highly purified Th17 cells from BDC2. 5NOD mice convert into Th1-like cells in NOD/SCID recipient mice D Bending, H De La Peña, M Veldhoen, JM Phillips, C Uyttenhove, ... The Journal of clinical investigation 119 (3), 565-572 , 2009 2009 Citations: 746
Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells M Veldhoen, K Hirota, J Christensen, A O'Garra, B Stockinger Journal of Experimental Medicine 206 (1), 43-49 , 2009 2009 Citations: 668
Microbiota derived short chain fatty acids promote histone crotonylation in the colon through histone deacetylases R Fellows, J Denizot, C Stellato, A Cuomo, P Jain, E Stoyanova, S Balázsi, ... Nature communications 9 (1), 105 , 2018 2018 Citations: 586
Interleukin 17 is a chief orchestrator of immunity M Veldhoen Nature immunology 18 (6), 612-621 , 2017 2017 Citations: 577
Signals mediated by transforming growth factor-β initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease M Veldhoen, RJ Hocking, RA Flavell, B Stockinger Nature immunology 7 (11), 1151-1156 , 2006 2006 Citations: 574
Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose M Saraiva, JR Christensen, M Veldhoen, TL Murphy, KM Murphy, ... Immunity 31 (2), 209-219 , 2009 2009 Citations: 455
Multi-tissue DNA methylation age predictor in mouse OSWR Thomas M. Stubbs, Marc Jan Bonder, Anne-Katrien Stark, Felix Krueger ... Genome biology 18 (1), 68 , 2017 2017 Citations: 443
Th17 T cells: linking innate and adaptive immunity B Stockinger, M Veldhoen, B Martin Seminars in immunology 19 (6), 353-361 , 2007 2007 Citations: 409
Persistence of skin-resident memory T cells within an epidermal niche A Zaid, LK Mackay, A Rahimpour, A Braun, M Veldhoen, FR Carbone, ... Proceedings of the National Academy of Sciences 111 (14), 5307-5312 , 2014 2014 Citations: 376
CD25 + CD4 + T cells compete with naive CD4 + T cells for IL-2 and exploit it for the induction of IL-10 production T Barthlott, H Moncrieffe, M Veldhoen, CJ Atkins, J Christensen, A O'Garra, ... International immunology 17 (3), 279-288 , 2005 2005 Citations: 320
Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH 17 cells and preserving group 3 innate lymphoid cells DR Withers, MR Hepworth, X Wang, EC Mackley, EE Halford, EE Dutton, ... Nature medicine 22 (3), 319-323 , 2016 2016 Citations: 284
