T-cells
The fighters of the adaptive immune system
Credit: Art by Nelli Aghekyan. Set in motion by Dr. Emanuele Petretto. Words by Dr. Suruchi Poddar. Project Coordinator: Dr. Masia Maksymowicz. Series Director: Dr. Radhika Patnala
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The T-cell family
Remember the 1984 movie “Terminator” starring Arnold Schwarzenegger as the cyborg/killing machine who wouldn’t stop till he had carried out his task? T-cells are a lot like the terminator. The only difference being, the terminator was sent from the future to wipe out mankind whereas T-cells are produced in each and every individual’s body to protect them from harmful pathogens and keep them away from diseases.
T-cells, also known as T-lymphocytes, serve as the major contributors of the adaptive immunity in vertebrates. They send signals to the immune system to safeguard the body against threats such as viruses, bacteria, allergens and even cancerous cells (1). Cytotoxic T-cells and helper T-cells are the predominant types of T-lymphocytes and exhibit characteristics true to what their names suggest. Cytotoxic T-cells are toxic for their targets (=pathogens) and helper T-cells help other immune cells (2). Cluster of differentiation (CD) is a molecule or a group of molecules expressed on the surface of a cell and is highly specific to that cell type. It is typically followed by a number from 1 to 400 such as CD3, CD26, CD371 etc. For example, a cell expressing a CD4 molecule is called CD4+ (CD4 positive) and a cell expressing a CD8 molecule is called CD8+ (CD8 positive) (3,4). Cytotoxic T-cells are CD8+ cells whose primary job is to eliminate virally infected cells, bacteria and malignant cancer cells by inducing apoptosis (destroying a cell from inside out) (5). Helper T-cells are CD4+ cells and play a significant role in steering immune responses (6). They help in the activation of cytotoxic T-cells in order to kill the target cells and in activation of B-cells to secrete antibodies and macrophages (7). Cytotoxic and helper T-cells play equally important roles in producing inflammatory cytokines such as interferon-γ (IFN-γ), tumour necrosis factor-α (TNF-α) and TNF-β that activate the immune system and protect the human body against microbial infections (8).
Two less common types of T-lymphocytes are regulatory T-cells and memory T-cells, the understated but indispensable types of T-lymphocytes that are associated with regulating the autoimmune response and building immunological tolerance, respectively (9).
The rise of the T-cells and their activation
T-cells originate from the bone marrow progenitor cells and migrate towards the thymus. Actually, T-cells derive their name from the thymus where they mature and differentiate into different types of T-cells. Eventually, T-cells lead their way into the lymph or bloodstream where they encounter antigens, pathogens and other small molecules that help them become activated and keep immune responses in check (1). For T-cells to work, they need to be activated. A complete orchestra of cells and glycoprotein complexes are required to trigger the terminator mode of T-cells. They can recognize an antigen or a foreign particle only when a special type of cell called antigen presenting cell (APC) attaches the antigen on the major histocompatibility complex (MHC) (a glycoprotein). The T-cells then bind to their respective MHCs i.e., cytotoxic T-cells bind to MHC-I and helper T-cells bind to MHC-II, and undergo activation (5). Once the fighter mode is “ON” T-cells provide potent and long-term protection from multiple environmental threats at different stages of life.
T-cells can be identified in nearly every organ and tissue in the body including primary and secondary lymphoid tissue, fat, mucosal barriers, brain and central nervous system. Bone marrow, spleen, tonsils, lymph nodes are considered rich in T-cells along with skin and peripheral human blood which also contain 2–3% of the total T-cell content (1). Some common abnormalities of T-cells include DiGeorge syndrome (which prevents healthy T-cell production), Hodgkin lymphoma (cancer of the lymphatic system), AIDS/human immunodeficiency virus (HIV) which attacks the CD4+ T-cells.
The inflection point of cancer treatment: CAR T-cell therapy
For decades, surgery, chemotherapy, and radiation therapy have been the major forms of cancer treatment. Although these treatments hold the upper hand, clinicians have started embracing newer forms of treatment which marks the beginning of the adoptive cell therapy (ACT) (10). A major breakthrough towards the new treatment paradigm is the chimeric antigen receptor (CAR) T-cell therapy. CAR T-cell therapy is a form of immunotherapy that genetically alters a patient’s own (autologous) T-cells to fight against cancer. Briefly, the process of CAR T-cell therapy starts with collection of a patient’s blood and isolation of T-cells from it. The obtained T-cells are then engineered, enhanced and endowed with special gears (DNA constructs) which help them to produce and express CARs. CARs are exclusive fusion proteins personalized for each individual patient that improves the potency of the compromised T-cell receptors to target and kill cancer cells. The genetically modified CAR T-cells are grown in the laboratory and infused intravenously into the patient (11). Since its approval in 2017 by the food and drug administration (FDA) CAR T-cell therapy has been used in the treatment of B-cell malignancies and multiple myeloma. Based on the encouraging results obtained from mitigating the symptoms of B-cell chronic lymphocytic leukemia, in one of the clinical trials, scientists are now testing the therapy for systemic lupus erythematosus (SLE), an autoimmune disease. Just like every other therapy, CAR T-cell therapy has its own limitations and challenges. It is extremely expensive, the most recently approved therapy costing more than $450,000. Furthermore, it has limited effectiveness against solid tumours (12). CAR T-cell therapy is an incredible treatment option, but refinement in the field is still ongoing to benefit a broad range of cancer patients in the near future.
Recognizing and appreciating the labs working in this space
- Dr. Saad J. Kendarian, T Cell Engineering Laboratory, Mayo Clinic. Minnesota, USA. https://www.mayo.edu/research/labs/t-cell-engineering/overview
- June Lab, Perelman School of Medicine, University of Pennsylvania. Pennsylvania, USA. https://www.med.upenn.edu/junelab/research-interests.html
- Maus Lab, Krantz Family Center for Cancer Research, Massachusetts General Hospital. Massachusetts, USA. https://mauslab.com/
- Mackall Lab, Stanford Center for Cancer Cell Therapy, Stanford University. California, USA. https://med.stanford.edu/mackalllab/research.html Twitter: @StanfordMed
- Yee Laboratory, MD Anderson Cancer Center, The University of Texas. Texas ,USA. https://www.mdanderson.org/research/departments-labs-institutes/labs/yee-laboratory.html Twitter: @MDAndersonNews
- Srivastava Lab, Fred Hutch Cancer Center, Seattle. Washington, USA. https://research.fredhutch.org/srivastava/en/research.html Twitter: @fredhutch
- Immuneel Therapeutics Private Ltd., Karnataka. Bangalore, India. https://immuneel.com/
- Autolus Therapeutics, London, UK. https://www.autolus.com/
- T cell Therapeutics Research Laboratories, City of Hope. California, USA. https://www.cityofhope.org/research/car-t-cell-therapy/t-cell-therapeutics-research-laboratories Twitter: @cityofhope
- The Sen Lab, Center for Cancer Research, Harvard Medical School. Massachusetts, USA. https://senlab.mgh.harvard.edu/research/ Twitter: @DebattamaSen
References
- Kumar, Brahma V et al. “Human T Cell Development, Localization, and Function throughout Life.” Immunity vol. 48,2 (2018): 202–213. doi:10.1016/j.immuni.2018.01.007
- Chopp, Laura et al. “From thymus to tissues and tumors: A review of T-cell biology.” The Journal of allergy and clinical immunology vol. 151,1 (2023): 81–97. doi:10.1016/j.jaci.2022.10.011
- Clark, Georgina, et al. “Nomenclature of CD Molecules from the Tenth Human Leucocyte Differentiation Antigen Workshop.” Clinical & Translational Immunology, vol. 5, no. 1, Jan. 2016, p. e57. PubMed Central, https://doi.org/10.1038/cti.2015.38.
- M.Sc, Michael Greenwood. “What Are CD Markers?” News-Medical, 15 Jan. 2021, https://www.news-medical.net/life-sciences/What-are-CD-Markers.aspx.
- Sun, Lina et al. “T cells in health and disease.” Signal transduction and targeted therapy vol. 8,1 235. 19 Jun. 2023, doi:10.1038/s41392–023–01471-y
- Wan, Yisong Y. “Multi-tasking of helper T cells.” Immunology vol. 130,2 (2010): 166–71. doi:10.1111/j.1365–2567.2010.03289.x
- Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. Helper T Cells and Lymphocyte Activation. Available from: https://www.ncbi.nlm.nih.gov/books/NBK26827/
- Cavalcanti, Yone Vila Nova et al. “Role of TNF-Alpha, IFN-Gamma, and IL-10 in the Development of Pulmonary Tuberculosis.” Pulmonary medicine vol. 2012 (2012): 745483. doi:10.1155/2012/745483
- Sciences, Akadeum Life. “Types of T Cells: Function and Activation of T Lymphocytes | Akadeum.” Akadeum Life Sciences, 26 Oct. 2020, https://www.akadeum.com/blog/different-types-of-t-cells/.
- De Marco, Rodrigo C et al. “CAR T Cell Therapy: A Versatile Living Drug.” International journal of molecular sciences vol. 24,7 6300. 27 Mar. 2023, doi:10.3390/ijms24076300
- CAR T Cells: Engineering Immune Cells to Treat Cancer — NCI. 12 June 2013, https://www.cancer.gov/about-cancer/treatment/research/car-t-cells.
- Mitra, Aroshi et al. “From bench to bedside: the history and progress of CAR T cell therapy.” Frontiers in immunology vol. 14 1188049. 15 May. 2023, doi:10.3389/fimmu.2023.1188049
About the author:
DR. SURUCHI PODDAR
Content Editor The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Poddar received a PhD in Biomedical Engineering from Indian Institute of Technology-Banaras Hindu University (IIT-BHU), Varanasi, India. She started her career as a postdoctoral researcher in 2020 with the Nanoscience Technology Center at the University of Central Florida, Orlando where she worked on a multi-organ human-on-a-chip system. Currently she is working on solid-state nanopore technology at Wake Forest University, North Carolina. When not working, she enjoys watching movies, cooking food and exploring new places, restaurants, attractions.
About the artist:
NELLY AGHEKYAN
Contributing Artist The League of Extraordinary Cell Types, Sci-Illustrate Stories
Nelli Aghekyan did a bachelor’s and master’s in Architecture in Armenia, after studying architecture and interior design for 6 years, she concentrated on her drawing skills and continued her path in the illustration world. She works mainly on children’s book illustrations, some of her books are now being published. Currently living in Italy, she works as a full-time freelance artist, collaborating with different companies and clients.
About the animator:
DR. EMANUELE PETRETTO
Animator The League of Extraordinary Cell Types, Sci-Illustrate Stories
Dr. Petretto received his Ph.D. in Biochemistry at the University of Fribourg, Switzerland, focusing on the behavior of matter at nanoscopic scales and the stability of colloidal systems. Using molecular dynamics simulations, he explored the delicate interaction among particles, interfaces, and solvents.
Currently, he is fully pursuing another delicate interaction: the intricate interplay between art and science. Through data visualization, motion design, and games, he wants to show the wonders of the complexity surrounding us.
About the series:
The League of Extraordinary Cell types
The team at Sci-Illustrate and Endosymbiont bring to you an exciting series where we dive deep into the wondrous cell types in our body, that make our hearts tick ❤.
