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In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity

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

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 34807

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Prof. Dr. Dieter Kabelitz

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Guest Editor

Institute of Immunology, Christian-Albrechts University of Kiel, Kiel, Germany
Interests: human gamma/delta T cells; T-cell activation; adoptive immunotherapy; tumor immunology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

For over 100 years, ground-breaking results of immunological research have been awarded with the Nobel Prize in Physiology or Medicine. Nobel Prizes have been awarded for outstanding research on various aspects of humoral immunity including the complement system (Bordet, 1919), the chemical structure of antibodies (Edelman and Porter, 1972), the immune network and the discovery of monoclonal antibodies (Jerne, Köhler and Milstein, 1984), and the discovery of somatic gene rearrangement during antibody formation (Tonegawa, 1987).

The current Special Issue of Cells is devoted to the memory of ground-breaking research in cellular immunology, and how such discoveries have paved the way for today’s understanding of cell-mediated immunity controlling innate and adaptive immune responses. Such milestones include the discovery of macrophages (Metchnikoff, Nobel Prize together with Ehrlich in 1908), the conceptualization of immunological tolerance (Medawar and Macfarlane Burnett, 1960), the discovery of MHC molecules (Benacerraf, Dausset and Snell, 1980), the discovery of MHC-restricted T-cell antigen recognition (Doherty and Zinkernagel, 1996), the identification of innate immune receptors and the role of dendritic cells (Beutler, Hoffmann and Steinman, 2011), and the recent recognition of the importance of negative immune regulation in cancer therapy (Allison and Honjo, 2018).

This Special Issue aims to collect papers in the field of cellular immunology with a focus on articles that illustrate how early ground-breaking work awarded with a Nobel Prize has influenced top-notch research until the present day. In this sense, we welcome articles dealing with immune cells and their role in innate and adaptive immunity.

Prof. Dr. Dieter Kabelitz
Guest Editor

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Keywords

dendritic cells
granulocytes
infection
Innate lymphoid cells
macrophages
T lymphocytes
tumor immunology

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Published Papers (10 papers)

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Research

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16 pages, 2844 KiB

Open AccessArticle

Prognostic Immune Effector Signature in Adult Acute Lymphoblastic Leukemia Patients Is Dominated by γδ T Cells

by Anne-Charlotte Le Floch, Marie-Sarah Rouvière, Nassim Salem, Amira Ben Amara, Florence Orlanducci, Norbert Vey, Laurent Gorvel, Anne-Sophie Chretien and Daniel Olive

Cells 2023, 12(13), 1693; https://doi.org/10.3390/cells12131693 - 22 Jun 2023

Cited by 4 | Viewed by 1640

Abstract

The success of immunotherapy has highlighted the critical role of the immune microenvironment in acute lymphoblastic leukemia (ALL); however, the immune landscape in ALL remains incompletely understood and most studies have focused on conventional T cells or NK cells. This study investigated the prognostic impact of circulating γδ T-cell alterations using high-dimensional analysis in a cohort of newly diagnosed adult ALL patients (10 B-ALL; 9 Philadelphia⁺ ALL; 9 T-ALL). Our analysis revealed common alterations in CD8⁺ T cells and γδ T cells of relapsed patients, including accumulation of early stage differentiation and increased expression of BTLA and CD73. We demonstrated that the circulating γδ T-cell signature was the most discriminating between relapsed and disease-free groups. In addition, Vδ2 T-cell alterations strongly discriminated patients by relapse status. Taken together, these data highlight the role of ɣδ T cells in adult ALL patients, among whom Vδ2 T cells may be a pivotal contributor to T-cell immunity in ALL. Our findings provide a strong rationale for further monitoring and potentiating Vδ2 T cells in ALL, including in the autologous setting. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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18 pages, 3544 KiB

Open AccessArticle

Characterization of BV6-Induced Sensitization to the NK Cell Killing of Pediatric Rhabdomyosarcoma Spheroids

by Vinzenz Särchen, Lisa Marie Reindl, Sara Wiedemann, Senthan Shanmugalingam, Thomas Bukur, Julia Becker, Martin Suchan, Evelyn Ullrich and Meike Vogler

Cells 2023, 12(6), 906; https://doi.org/10.3390/cells12060906 - 15 Mar 2023

Viewed by 2437

Abstract

Although the overall survival in pediatric rhabdomyosarcoma (RMS) has increased over the last decades, the most aggressive subtype of alveolar RMS is in dire need of novel treatment strategies. RMS cells evade cell death induction and immune control by increasing the expression of inhibitors of apoptosis proteins (IAPs), which can be exploited and targeted with stimulation with Smac mimetics. Here, we used the Smac mimetic BV6 to re-sensitize RMS spheroids to cell death, which increased killing induced by natural killer (NK) cells. Single BV6 treatment of RMS spheroids did not reduce spheroidal growth. However, we observed significant spheroidal decomposition upon BV6 pre-treatment combined with NK cell co-cultivation. Molecularly, IAPs s are rapidly degraded by BV6, which activates NF-κB signal transduction pathways in RMS spheroids. RNA sequencing analysis validated NF-κB activation and identified a plethora of BV6-regulated genes. Additionally, BV6 released caspases from IAP-mediated inhibition. Here, caspase-8 might play a major role, as knockdown experiments resulted in decreased NK cell-mediated attack. Taken together, we improved the understanding of the BV6 mechanism of RMS spheroid sensitization to cytotoxic immune cells, which could be suitable for the development of novel combinatory cellular immunotherapy with Smac mimetics. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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27 pages, 7126 KiB

Open AccessEditor’s ChoiceArticle

Dendritic Cells or Macrophages? The Microenvironment of Human Clear Cell Renal Cell Carcinoma Imprints a Mosaic Myeloid Subtype Associated with Patient Survival

by Dorothee Brech, Anna S. Herbstritt, Sarah Diederich, Tobias Straub, Evangelos Kokolakis, Martin Irmler, Johannes Beckers, Florian A. Büttner, Elke Schaeffeler, Stefan Winter, Matthias Schwab, Peter J. Nelson and Elfriede Noessner

Cells 2022, 11(20), 3289; https://doi.org/10.3390/cells11203289 - 19 Oct 2022

Cited by 5 | Viewed by 3760

Abstract

Since their initial description by Elie Metchnikoff, phagocytes have sparked interest in a variety of biologic disciplines. These important cells perform central functions in tissue repair and immune activation as well as tolerance. Myeloid cells can be immunoinhibitory, particularly in the tumor microenvironment, where their presence is generally associated with poor patient prognosis. These cells are highly adaptable and plastic, and can be modulated to perform desired functions such as antitumor activity, if key programming molecules can be identified. Human clear cell renal cell carcinoma (ccRCC) is considered immunogenic; yet checkpoint blockades that target T cell dysfunction have shown limited clinical efficacy, suggesting additional layers of immunoinhibition. We previously described “enriched-in-renal cell carcinoma” (erc) DCs that were often found in tight contact with dysfunctional T cells. Using transcriptional profiling and flow cytometry, we describe here that ercDCs represent a mosaic cell type within the macrophage continuum co-expressing M1 and M2 markers. The polarization state reflects tissue-specific signals that are characteristic of RCC and renal tissue homeostasis. ErcDCs are tissue-resident with increasing prevalence related to tumor grade. Accordingly, a high ercDC score predicted poor patient survival. Within the profile, therapeutic targets (VSIG4, NRP1, GPNMB) were identified with promise to improve immunotherapy. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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27 pages, 4780 KiB

Open AccessReview

Mononuclear Phagocytes, Cellular Immunity, and Nobel Prizes: A Historic Perspective

by Siamon Gordon, Annabell Roberti and Stefan H. E. Kaufmann

Cells 2024, 13(16), 1378; https://doi.org/10.3390/cells13161378 - 19 Aug 2024

Viewed by 1336

Abstract

The mononuclear phagocyte system includes monocytes, macrophages, some dendritic cells, and multinuclear giant cells. These cell populations display marked heterogeneity depending on their differentiation from embryonic and bone marrow hematopoietic progenitors, tissue location, and activation. They contribute to tissue homeostasis by interacting with local and systemic immune and non-immune cells through trophic, clearance, and cytocidal functions. During evolution, they contributed to the innate host defense before effector mechanisms of specific adaptive immunity emerged. Mouse macrophages appear at mid-gestation and are distributed throughout the embryo to facilitate organogenesis and clear cells undergoing programmed cell death. Yolk sac, AGM, and fetal liver-derived tissue-resident macrophages persist throughout postnatal and adult life, supplemented by bone marrow-derived blood monocytes, as required after injury and infection. Nobel awards to Elie Metchnikoff and Paul Ehrlich in 1908 drew attention to cellular phagocytic and humoral immunity, respectively. In 2011, prizes were awarded to Jules Hoffmann and Bruce Beutler for contributions to innate immunity and to Ralph Steinman for the discovery of dendritic cells and their role in antigen presentation to T lymphocytes. We trace milestones in the history of mononuclear phagocyte research from the perspective of Nobel awards bearing directly and indirectly on their role in cellular immunity. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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12 pages, 2008 KiB

Open AccessReview

“All for One and One for All”: The Secreted Heat Shock Protein gp96-Ig Based Vaccines

by Laura Padula, Eva Fisher and Natasa Strbo

Cells 2024, 13(1), 72; https://doi.org/10.3390/cells13010072 - 29 Dec 2023

Viewed by 1943

Abstract

It has been 50 years since Peter Charles Doherty and Rolf M Zinkernagel proposed the principle of “simultaneous dual recognition”, according to which adaptive immune cells recognized “self” and “non-self” simultaneously to establish immunological efficacy. These two scientists shared the 1996 Nobel Prize in Physiology or Medicine for this discovery. Their basic immunological principle became the foundation for the development of numerous vaccine approaches against infectious diseases and tumors, including promising strategies grounded on the use of recombinant gp96-Ig developed by our lab over the last two decades. In this review, we will highlight three major principles of the gp96-Ig vaccine strategy: (1) presentation of pathogenic antigens to T cells (specificity); (2) activation of innate immune responses (adjuvanticity); (3) priming of T cells to home to the epithelial compartments (mucosal immunity). In summary, we provide a paradigm for a vaccine approach that can be rapidly engineered and customized for any future pathogens that require induction of effective tissue-resident memory responses in epithelial tissues. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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18 pages, 1136 KiB

Open AccessReview

Organoids as an Enabler of Precision Immuno-Oncology

by Junzhe Zhao, Antoinette Fong, See Voon Seow and Han Chong Toh

Cells 2023, 12(8), 1165; https://doi.org/10.3390/cells12081165 - 14 Apr 2023

Cited by 4 | Viewed by 3655

Abstract

Since the dawn of the past century, landmark discoveries in cell-mediated immunity have led to a greater understanding of the innate and adaptive immune systems and revolutionised the treatment of countless diseases, including cancer. Today, precision immuno-oncology (I/O) involves not only targeting immune checkpoints that inhibit T-cell immunity but also harnessing immune cell therapies. The limited efficacy in some cancers results mainly from a complex tumour microenvironment (TME) that, in addition to adaptive immune cells, comprises innate myeloid and lymphoid cells, cancer-associated fibroblasts, and the tumour vasculature that contribute towards immune evasion. As the complexity of TME has called for more sophisticated human-based tumour models, organoids have allowed the dynamic study of spatiotemporal interactions between tumour cells and individual TME cell types. Here, we discuss how organoids can study the TME across cancers and how these features may improve precision I/O. We outline the approaches to preserve or recapitulate the TME in tumour organoids and discuss their potential, advantages, and limitations. We will discuss future directions of organoid research in understanding cancer immunology in-depth and identifying novel I/O targets and treatment strategies. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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14 pages, 14733 KiB

Open AccessReview

Tumor-Infiltrating Dendritic Cells: Decisive Roles in Cancer Immunosurveillance, Immunoediting, and Tumor T Cell Tolerance

by Theodora Katopodi, Savvas Petanidis, Charalampos Charalampidis, Ioanna Chatziprodromidou, Panagiotis Eskitzis, Drosos Tsavlis, Paul Zarogoulidis, Christoforos Kosmidis, Dimitris Matthaios and Konstantinos Porpodis

Cells 2022, 11(20), 3183; https://doi.org/10.3390/cells11203183 - 11 Oct 2022

Cited by 20 | Viewed by 3307

Abstract

The tumor microenvironment plays a key role in progression of tumorigenesis, tumor progression, and metastasis. Accumulating data reveal that dendritic cells (DCs) appear to play a key role in the development and progression of metastatic neoplasia by driving immune system dysfunction and establishing immunosuppression, which is vital for tumor evasion of host immune response. Consequently, in this review, we will discuss the function of tumor-infiltrating DCs in immune cell signaling pathways that lead to treatment resistance, tumor recurrence, and immunosuppression. We will also review DC metabolism, differentiation, and plasticity, which are essential for metastasis and the development of lung tumors. Furthermore, we will take into account the interaction between myeloid cells and DCs in tumor-related immunosuppression. We will specifically look into the molecular immune-related mechanisms in the tumor microenvironment that result in reduced drug sensitivity and tumor relapse, as well as methods for combating drug resistance and focusing on immunosuppressive tumor networks. DCs play a crucial role in modulating the immune response. Especially, as cancer progresses, DCs may switch from playing an immunostimulatory to an inhibitory role. This article’s main emphasis is on tumor-infiltrating DCs. We address how they affect tumor growth and expansion, and we highlight innovative approaches for therapeutic modulation of these immunosuppressive DCs which is necessary for future personalized therapeutic approaches. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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12 pages, 1442 KiB

Open AccessReview

Of Flies and Men—The Discovery of TLRs

by Hauke Johannes Weiss and Luke Anthony John O’Neill

Cells 2022, 11(19), 3127; https://doi.org/10.3390/cells11193127 - 5 Oct 2022

Cited by 11 | Viewed by 3642

Abstract

In 2011, the Nobel Prize in Physiology or Medicine was awarded to three immunologists: Bruce A. Beutler, Jules A. Hoffmann, and Ralph M. Steinman. While Steinman was honored for his work on dendritic cells and adaptive immunity, Beutler and Hoffman received the prize for their contributions to discoveries in innate immunity. In 1996, Hoffmann found the toll gene to be crucial for mounting antimicrobial responses in fruit flies, first implicating this developmental gene in immune signaling. Two years later, Beutler built on this observation by describing a Toll-like gene, tlr4, as the receptor for the bacterial product LPS, representing a crucial step in innate immune activation and protection from bacterial infections in mammals. These publications spearheaded research in innate immune sensing and sparked a huge interest regarding innate defense mechanisms in the following years and decades. Today, Beutler and Hoffmann’s research has not only resulted in the discovery of the role of multiple TLRs in innate immunity but also in a much broader understanding of the molecular components of the innate immune system. In this review, we aim to collect the discoveries leading up to the publications of Beutler and Hoffmann, taking a close look at how early advances in both developmental biology and immunology converged into the research awarded with the Nobel Prize. We will also discuss how these discoveries influenced future research and highlight the importance they hold today. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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15 pages, 2636 KiB

Open AccessReview

Reprogramming T-Cell Metabolism for Better Anti-Tumor Immunity

by Yu Ping, Chunyi Shen, Bo Huang and Yi Zhang

Cells 2022, 11(19), 3103; https://doi.org/10.3390/cells11193103 - 1 Oct 2022

Cited by 10 | Viewed by 4590

Abstract

T cells play central roles in the anti-tumor immunity, whose activation and differentiation are profoundly regulated by intrinsic metabolic reprogramming. Emerging evidence has revealed that metabolic processes of T cells are generally altered by tumor cells or tumor released factors, leading to crippled anti-tumor immunity. Therefore, better understanding of T cell metabolic mechanism is crucial in developing the next generation of T cell-based anti-tumor immunotherapeutics. In this review, we discuss how metabolic pathways affect T cells to exert their anti-tumor effects and how to remodel the metabolic programs to improve T cell-mediated anti-tumor immune responses. We emphasize that glycolysis, carboxylic acid cycle, fatty acid oxidation, cholesterol metabolism, amino acid metabolism, and nucleotide metabolism work together to tune tumor-reactive T-cell activation and proliferation. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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23 pages, 2838 KiB

Open AccessReview

Application and Design of Switches Used in CAR

by Paweł Głowacki and Piotr Rieske

Cells 2022, 11(12), 1910; https://doi.org/10.3390/cells11121910 - 13 Jun 2022

Cited by 5 | Viewed by 5886

Abstract

Among the many oncology therapies, few have generated as much excitement as CAR-T. The success of CAR therapy would not have been possible without the many discoveries that preceded it, most notably, the Nobel Prize-winning breakthroughs in cellular immunity. However, despite the fact that CAR-T already offers not only hope for development, but measurable results in the treatment of hematological malignancies, CAR-T still cannot be safely applied to solid tumors. The reason for this is, among other things, the lack of tumor-specific antigens which, in therapy, threatens to cause a lethal attack of lymphocytes on healthy cells. In the case of hematological malignancies, dangerous complications such as cytokine release syndrome may occur. Scientists have responded to these clinical challenges with molecular switches. They make it possible to remotely control CAR lymphocytes after they have already been administered to the patient. Moreover, they offer many additional capabilities. For example, they can be used to switch CAR antigenic specificity, create logic gates, or produce local activation under heat or light. They can also be coupled with costimulatory domains, used for the regulation of interleukin secretion, or to prevent CAR exhaustion. More complex modifications will probably require a combination of reprogramming (iPSc) technology with genome editing (CRISPR) and allogenic (off the shelf) CAR-T production. Full article

(This article belongs to the Special Issue In Honor of Nobel Prize in Physiology or Medicine: Cell-Mediated Immunity)

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