TBNK cells: What are They and What Can They Tell Us?
White blood cells, or leukocytes, make up only about 1% of the blood. But they play a critical role in the immune system, and they can tell researchers a lot in studies.
Among these leukocytes, lymphocytes — T cells, B cells, and NK cells — all come from a common lymphoid progenitor (CLP) in the hematopoietic stem cell lineage. They share this common origin, but each type has a specialized job. Together, they drive the innate and adaptive immune responses.
The immune system plays some role in almost every disease. Identifying and characterizing the many subtypes of TBNK cells and other immune factors can reveal key biomarkers tied to a specific disease. Researchers can then use these biomarkers in clinical development programs as secondary or exploratory endpoints, to check for immune-related adverse events, or to measure a drug’s efficacy.
Tracking how immune cell subtypes and cytokines change during natural disease progression can also reveal potential targets for immunomodulation in treatment development.1 On top of that, people with the same disease can show differences in certain activated cell markers and cytokines. These differences point to distinct disease phenotypes, which helps researchers group patients in trials and develop more personalized treatments.
Broadly speaking, an immune response starts when the innate immune system recognizes a foreign invader or cancerous cell. This triggers cytokine release, complement activation, and acute inflammation. That fast reaction then triggers a more targeted response from the adaptive immune system, which relies on antigen-presenting cells to activate specific T helper cells. These activated T cells coordinate an antigen-specific immune response that involves humoral immunity from B cells and cell-mediated immunity from other T cells. This is a simplified picture — many other cell types and factors work together to drive complex signaling cascades that keep the immune system running properly.
Development and Function of T Cells
T cells start differentiating in the bone marrow. They then migrate to the thymus gland to mature into thymocytes. T cells attack foreign cells, cancer cells, and virus-infected cells — almost like detectives that scope out pathogens through a unique T cell receptor that develops during maturation. T cell progenitor cells can turn into three main subtypes:
- T helper 1 lymphocytes (Th1 cells) — drive inflammatory reactions and immunity to intracellular microbes.
- T helper 2 lymphocytes (Th2 cells) — mainly help B lymphocytes produce antibodies, and also help tone down the inflammatory activity of Th1 cells.
- Cytotoxic T (Tc) cells — clear virus-infected cells and tumor cells, typically by triggering apoptosis.
Many T cell subsets respond to infection. This response also drives the formation of memory T cells, which recognize specific antigens and stand ready for the next infection.
T cells release various cytokines — TNF-α, TNF-β, interferon-γ, IL-2, IL-4, IL-6, and IL-8 — that trigger downstream activation of other immune cells and responses. IL-2, for example, gets upregulated in T cells after antigenic or mitogenic stimulation, which can drive clonal expansion of T cells. Many of these cytokines also activate and recruit other cell types, such as B cells, NK cells, macrophages, and neutrophils.2
Antigen-presenting cells — including B cells, macrophages, and dendritic cells — along with natural killer cells, can further activate T cell functions. This shows how much these cell types communicate with each other. The innate and adaptive immune responses are genuinely complex, and many of these factors overlap in function, acting as fail-safes that keep immune regulation working properly. By mapping these relationships in both normal and disease states, researchers can identify targets for drug development that harness or repair these cell functions to fight disease.
Development and Function of B Cells
B cell progenitor cells in the bone marrow migrate to the lymph nodes, where they differentiate into immature B cells. B cells make antibodies that help the body fight infections, and they play a critical role in building the adaptive immune response to specific antigens. When exposed to an antigen, naïve B cells differentiate into either plasma cells or memory cells.
- Plasma cells produce and release specific antibodies into the blood that recognize a particular antigen. These free-floating antibodies bind to cell- or pathogen-based antigens and trigger a signaling cascade that recruits many different cell types to attack that cell and other infected cells like it.
- Memory cells are long-lived lymphocytes that carry the code to produce a particular antibody, but they don’t produce antibodies directly unless activated to differentiate into plasma cells.
Memory cells typically activate when an antigen reappears, long after the first exposure. This happens much faster than the process of naïve B cells differentiating into plasma or memory cells. It’s how the immune system “remembers” past pathogens without flooding the blood with unnecessary antibodies. Among the cytokines B cells secrete is IL-6, the primary driver of fever, hormone changes, and T and B cell expansion after injury or infection.2 Over time, plasma cells and the antibodies they produce decrease in number, leaving memory cells to take over antibody production if the antigen shows up again.
Development and Function of NK Cells
Natural killer (NK) cells produce substances that kill tumor cells or virus-infected cells as part of the innate immune system. Think of them like poison darts aimed at infected cells — they can also recruit other factors to finish the job. NK cells make up only a small fraction of the total lymphocyte population, yet they’re found throughout lymphoid and non-lymphoid tissues.3
Unlike most other immune cells, NK cells don’t need major histocompatibility complex class I (MHC-I) antigens or antibodies to do their cell-killing job. This lets them respond much faster to viral infection or cancerous cells. NK cells mainly rely on markers that signal a cell is in “distress,” but they can also detect antibody-coated target cells and take part in the antibody-dependent cell cytotoxicity pathway.
Among the cytokines NK cells secrete is IFN-γ, which mainly drives the antiviral response, activates macrophages, and helps clear intracellular mycobacteria.2 IFN-γ, also secreted by activated Th1 T cells, can stimulate macrophages, boost antigen processing and MHC molecule expression, promote Ig class switching, and control the growth of transformed cells.
How Are They Used in Research?
Profiling TBNK cells is foundational to immune-related research. It gives researchers valuable information on how patients respond to therapies and vaccines. Flow cytometry is a workhorse method for classifying and sorting specific cell subtypes using fluorescently labeled antibodies against extracellular and intracellular markers.4 Measuring cytokine levels through various assays sheds light on immune function and activation. TNF-α, for example, is a proinflammatory biomarker that researchers can track in studies of autoimmune disease progression and treatment evaluation.2
In vaccine development, characterizing the neutralizing or binding activity of antibodies, along with the various B and T cell subsets that drive cell-mediated immunity, tells researchers how strong and durable the immune response is after immunization. This matters a lot in early clinical development, where it helps guide dose selection and vaccination schedules, and informs the potential for efficacy that will need testing later in large-scale Phase 3 trials. Researchers can also use these immunogenicity endpoints in immunobridging studies, which extend the indication of an already-approved vaccine to populations that weren’t well represented in the original trials, such as pediatric patients — a practice that gained traction during the COVID pandemic.
Research that characterizes the unique cell subtypes found in various cancers has helped drive the development of many targeted cancer immunotherapies. These therapies work by blocking immune checkpoints, boosting T cell function, or delivering monoclonal antibodies to target specific antigens on cancer cells.5 In autoimmune diseases, on the other hand, certain immune cells attack “self” cells, so immunotherapies work to suppress or block that activity to control the disease.5 Even with these successes, many cancer patients and people with autoimmune diseases still don’t respond to immunotherapy, or they eventually develop resistance to it. Further research into the full repertoire of immune cell subsets activated during cancer development will help close this gap in treatment options.
Overall, understanding the role these various cell types play in infection responses, cancer development, and autoimmunity gives researchers valuable insight into how to modulate and target the immune system — to clear infections more effectively, control or eliminate tumor and cancer progression, and protect the body from attacking itself.
References
- Flower DR. The Immune System as Drug Target. Immunology and Immunogenetics Insights. (2013). https://doi:10.4137/III.S12145
- Cameron MJ, Kelvin DJ. Cytokines, Chemokines and Their Receptors. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013. Available from: https://www.ncbi.nlm.nih.gov/books/NBK6294/
- Vivier E, Tomasello E, Baratin M, Walzer T, Ugolini S. Functions of natural killer cells. Nat Immunol 9, 503–510 (2008). https://doi.org/10.1038/ni1582
- Mousset CM, Hobo W, Woestenenk R, Preijers F, Dolstra H, van der Waart AB. Comprehensive Phenotyping of T Cells Using Flow Cytometry. Cytometry. 2019 Jun;95(6):647–54.
- Melief CJM. Special Review: The future of Immunotherapy. Immunotherapy Advances. 2021 Jan 1;1(1):ltaa005.
