Markus Uhrberg
Andreas Radbruch- 1Institute of Transplantation Diagnostics and Cell Therapeutics, University Hospital of Düsseldorf, Düsseldorf, Germany
- 2Deutsches Rheuma-Forschungszentrum Berlin, a Leibniz Institute, Berlin, Germany
Editorial on the Research Topic
Global excellence in cellular immunology: Europe 2021
This Research Topic was set up to highlight recent progress in cellular immunology in Europe. Rather than focus on a particular smaller topic, it aims to shed light on recent progress made across the entire breadth of the cellular immunology field in Europe. Considering this, the present Research Topic hosts a small but nice collection of four articles highlighting the present key aspects of T cell and Natural Killer (NK) cell immunology: memory compartments, tissue-residency, checkpoint regulation, and mechanism of cytotoxicity. Of note, all articles focus on the human immune system, which we in general do understand less well than the murine immune system. Given the genetic and functional differences between human and mouse immune cells already known (1, 2), the need for a better understanding of the human immune system is obvious, in order to solve the many burning questions involved in avoiding and controlling infectious diseases, autoimmunity, and cancer. The field is hampered by the logistic and ethical constraints that are attached to working with tissue biopsies other than blood from patients or even harder, from healthy individuals. The research work presented here reflects the ongoing efforts to better understand how the human immune system works on the systemic level.
In the study by Haugstøyl et al., the surface proteome of NK cells residing in adipose tissue was characterized. Adipose tissue-resident NK cells have recently gained much interest from studies suggesting them to be mediators of inflammation and insulin resistance in obesity (3). So far, NK cells residing in human adipose tissue are poorly defined. The present study performed high-dimensional flow cytometric analyses on NK cells from subcutaneous (SAT) as well as visceral adipose tissue (VAT). The authors nicely illustrate how tissue-resident NK cells adapt to their specific microenvironment by defining protein signatures specific for VAT vs. SAT. Notably, VAT contained a higher frequency of immature tissue-resident NK cells compared to SAT, which is interesting given that the VAT/SAT ratio correlates with risk of cardiovascular disease and insulin resistance (4). Although a link between the presence of NK cell subsets and insulin resistance has not yet been established in the present study, the newly defined surface markers will be a valuable asset to explore if and how NK cells contribute to obesity-induced inflammatory stress and diabetes.
Another type of lymphocyte, absent from peripheral blood and a challenge to analyze, are human tissue-resident memory T cells (Trm) (5). When T cells enter a nonlymphoid organ in the effector phase of an immune response, a subset of them can develop in situ into Trm cells that remain in the tissue and do not recirculate anymore. Trm cells ensure their tissue-residency by acquisition of a specific set of receptors that varies between organs but typically involves upregulation of CD69 and downregulation of S1PR1 as well as other receptors enabling recirculation such as CCR7. In the tissue, upon reinfection, Trm can mount rapid antigen-specific recall responses, i.e. immunosurveillance at an early stage of infection. The focus of the present review by Ginsberg et al., are Trm cells residing in the kidney. The work illustrates the Janus-faced nature of this highly-sensitive memory T cell compartment, which provides antigen-specific immune protection against pathogens, but if autoreactive, can also promote autoimmune diseases. The review summarizes our knowledge on the role of pathogenic renal Trm in glomerulonephritis, emphasizing that most T cells in the kidney have a Trm phenotype and that their abundance correlates with disease severity. Finally, the authors discuss possible strategies to target pathogenic Trm in renal autoimmune disease based on metabolic inhibition, cytokine deprivation, or induction of antigen-specific tolerance with autoantigen-coated reagents.
Besides tissue resident Trm, effector memory (Tem) and central memory (Tcm) T cells circulating through blood and lymph provide systemic protection, by patrolling secondary lymphoid organs and migrating to inflamed nonlymphoid tissues (6). It is believed that Tem are more cytotoxic than Tcm cells, but a quantitative comparison including dissection of the cytotoxic mechanisms on the single cell level has been lacking. In their present work, Knörck et al. describe a FRET (Förster Resonance Energy Transfer)-based assay to distinguish between target cell apoptosis and necrosis on the single cell level. The study exemplifies the importance of cooperation across system boundaries, in this case a team of biophysicists employing a FRET reporter system developed by chemists (7) and applying it to basic immunology questions. The authors used a Casper3 FRET reporter with a caspase 3 cleavage site to monitor apoptosis and necrosis event, simultaneously tracking effector/target cell contact times by real-time microscopy. Tem were more efficient killers than Tcm and this correlated to higher perforin content, faster target cell contact and more efficient immune synapse formation. The new technique will aid to evaluate how different T cell subsets, for example in CAR-T cell therapy, contribute to tumor control.
Umbilical cord blood (CB) is another home of immune and hematopoietic cells of basic and applied interest. It not only is a source for allogeneic stem cells used for transplantation, but also holds great promise as a source for cell-based tumor therapy and the in vitro generation of immune cells with therapeutic potential that are rare in peripheral blood such as innate lymphoid cells (ILCs) and plasmacytoid dendritic cells (8–11). Here, Greppi et al. have identified a novel subpopulation of NK cells in CB that express the checkpoint inhibitor programmed death receptor 1 (PD1). The same group had previously shown that so-called adaptive NK cells, a population of memory NK cells specifically arising upon infection with human Cytomegalovirus (HCMV) could express PD-1 (12). It thus came as a surprise that PD1+ NK cells are also present in CB, which except for rare cases of mother-to-child transmission, had never been exposed to HCMV. Importantly, the authors were able to obtain CB from the child together with peripheral blood from the mother and could show that PD1+ NK cells arise independent of HCMV seropositivity of the mother. Notably, PD1+ NK cells were generally more responsive to target cell and cytokine stimulation whereas direct triggering of PD1 led to inhibition of PD1+ NK cells as expected. Given that PD1 checkpoint inhibition is widely used in treatment of cancer, it will be important to find out in how far this affects tumor-specific responses of CB-derived NK cells.
Altogether, the different contributions in this Research Topic provide an excellent display of recent advances in cellular immunology in Europe.
Author contributions
MU: Conceptualization, Writing – original draft, Writing – review & editing. AR: Conceptualization, Writing – original draft, Writing – review & editing.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
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Keywords: T cells, NK cells, tissue residency, memory, checkpoint inhibition
Citation: Uhrberg M and Radbruch A (2023) Editorial: Global excellence in cellular immunology: Europe 2021. Front. Immunol. 14:1283105. doi: 10.3389/fimmu.2023.1283105
Received: 25 August 2023; Accepted: 31 August 2023;
Published: 07 September 2023.
Edited and Reviewed by:
Mariolina Salio, Immunocore, United KingdomCopyright © 2023 Uhrberg and Radbruch. 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) and the copyright owner(s) 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: Markus Uhrberg, Markus.uhrberg@med.uni-duesseldorf.de