(Cover Illustration by Jenna Hughes)
Image Description: T-cell security patrolling harmful antigens
Introduction
Imagine the immune system as a high-tech security team, with T-cells combining the precision of facial recognition cameras and the force of a SWAT team in one. T-cell lymphocytes are a type of white blood cell responsible for fighting diseases. Protein receptors on the surface of such cells are known as T-cell receptors (TCR). Each TCR identifies and binds to a highly specific antigen (foreign molecules that trigger immune responses).
Although most T-cells have one exclusive TCR complex on their surface, like a singular key designed to fit a lock, some T-cells carry two TCRs, known as dual T-cell receptors. These cells are highly alloreactive.
What is the function of Dual TCR cells?
According to Nathaniel J Schuldt. et al, 10% to 30% of T-cells within mice and humans are dual TCR cells; however, researchers do not understand the extent of their function (The Journal of Immunology 2017). This finding ignited interest in studying the function of dual TCR cells. In other words, there is a combination of two varying VDJ receptor configurations. Thus, the immune cell can respond to multiple separate antigens, improving its efficiency.
The refined ability may make the immune system more flexible and responsive, but it also raises the question: Could having two receptors increase the chance of mistakenly attacking the body’s own cells?
How does MHC play a role in immune responses?
The major histocompatibility complex, known as MHC, is a set of surface proteins on antigen-presenting cells. Human leukocyte antigens (HLA) are a subset of the MHC complex solely present in humans. MHC and HLA are closely related as they both describe a group of genes responsible for encoding proteins involved in immune system recognition. The term MHC refers to this gene complex across all vertebrates, whereas HLA specifically denotes the human version of this complex. MHC genes are located on chromosome six and are categorized into three classes: class I, class II, and class III. The HLA genes are further divided into specific groups: HLA-A, HLA-B, and HLA-C (class I), HLA-DR, HLA-DP, and HLA-DQ (class II).
Only Class I and II MHC molecules present antigens. Class I MHC displays antigen molecules produced by cells within the body. This characteristic allows for self-recognition of molecules. On the other hand, Class II exposes extracellular pathogens or foreign invaders in the body. This identification feature is important in transplantation, since the mechanism of self-non-self recognition plays a critical role. When a recipient undergoes an organ transplant, patients must take immunosuppressants that inhibit this recognition mechanism in order to suppress immune activity. This precaution is necessary to prevent graft rejection of the transplanted organ or graft-versus-host disease, a transplant-induced disorder.
Several types of T-cells, including the T-helper cells, cytotoxic T-cells, and more, exist. These T-cells have receptors on their surfaces serving the role of recognizing MHC/HLA molecules. T-helper cells, also known as CD4+ cells, are conductors inducing immune responses through activation of immune cells (B-cells and macrophages). Cytotoxic T-cells, known as CD8+ cells, have an assassin-like role, killing all infected, cancerous, and damaged cells.
While CD8+ cells bind to an antigen highlighted by cells presenting Class I MHC, CD4+ cells recognize and bind to antigens exposed by MHC Class II molecules. Activation of T-cells is initiated by the binding process of T-cell receptors with antigens (signal one). To carry out the full activation mechanism, independent signals must be received after the binding. The next step requires various costimulatory signals from receptors on the membrane of the cell. T-helper cells rely on receptor CD28 to produce costimulatory signals and bind to ligand CD80 or CD89 on antigen-presenting cells. In return, this triggers the T-cell to proliferate, clone itself to make an army of T-cells able to recognize and combat the antigen it originally bound to. Lastly, the third signal begins with further instruction carried by cytokines, small proteins that serve as messengers in cell signaling interactions, shaping the development of appropriate defense cells required to attack the pathogen.
Can Dual TCR Cells worsen in autoimmune disorders?
In recent studies, researchers hypothesize that dual TCR cells increase the risk of autoimmune diseases (conditions where the immune system attacks the body’s own tissues). Developing T-cells go through a developmental process in the thymus (a small organ located between the lungs), to select against immune cells that may attack self-cells. However, if a T-cell has two receptors, one TCR may mediate selection even if the other is potentially dangerous. Nathaniel J Schuldt et al suggest that dual TCR cells contribute to autoimmunity by reducing the number of peacekeeper cells, making it easier for harmful immune attacks to occur (The Journal of Immunology 2017).
The experimental design behind this research finding includes using a special mouse model (NOD mice) that naturally develops type 1 diabetes, an autoimmune disease where the immune system attacks insulin-producing cells. Mice without dual TCRs were found to have greater regulatory T-cells (Tregs or “peacekeeper” cells), thereby reducing autoreactivity against the body’s own tissues. These T-reg cells are essential to regulating the cellular responses against threats, antigens and are responsible for limiting autoimmune attacks. A decrease in these cells is correlated with an increase in autoimmune attacks. The mice lacking dual T-cells were also protected from further developing diabetes.
In a transplant immunology study, dual T-cells were found to release signaling molecules that may harm the body’s own cells. Researchers Gerald Morris et. al. studied dual TCR T-cells in patients with acute graft-versus-host disease (GVHD). Acute GVHD is a complication that can occur after transplantation, in which the donor’s immune cells mistakenly attack the patient’s body. Findings show dual TCR T-cells as highly active and, when triggered, release harmful signaling molecules (cytokines) that worsen aGVHD. These immune cells are experts in recognizing the patient’s tissues as “foreign,” even when in minor instances of mismatch in genetic coding, thus making up a large portion of the immune response..
Researchers don’t fully understand why dual TCR T-cells are so prone to attacking the host. Findings suggest that removing these cells from donor material before transplantation may help prevent aGVHD, improving transplant success and patient safety.
Conclusion
Understanding the mechanisms behind dual TCR T-cells is essential because they challenge the traditional view of each T-cell only recognizing a singular target. By carrying two receptors, these cells may enhance immune flexibility but also increase the risk of harmful responses, such as autoimmunity or graft-versus-host disease. Research has shown a tendency for dual TCR T-cells to be antigen-experienced. Clarifying the role of dual TCRs can reveal why certain immune reactions become dangerous, improve transplant safety, and guide the design of more effective immunotherapies for cancer and other diseases.
Sources
Audehm, Stefan, et al. “Key features relevant to select antigens and TCR from the MHC-mismatched repertoire to treat cancer.” Frontiers in Immunology, vol. 10, 28 June 2019, https://doi.org/10.3389/fimmu.2019.01485.
Balakrishnan, Amritha, and Gerald P. Morris. “The highly alloreactive nature of dual TCR T cells.” Current Opinion in Organ Transplantation, vol. 21, no. 1, Feb. 2016, pp. 22–28, https://doi.org/10.1097/mot.0000000000000261.
Choo, Sung Yoon. “The HLA system: Genetics, immunology, clinical testing, and clinical implications.” Yonsei Medical Journal, vol. 48, no. 1, 2007, p. 11, https://doi.org/10.3349/ymj.2007.48.1.11.
Gavin, Marc A., and Alexander Y. Rudensky. “Dual TCR T cells: Gaining entry into the periphery.” Nature Immunology, vol. 3, no. 2, Feb. 2002, pp. 109–110, https://doi.org/10.1038/ni0202-109.
Morris, Gerald P., et al. “Dual receptor T cells mediate pathologic alloreactivity in patients with acute graft-versus-host disease.” Science Translational Medicine, vol. 5, no. 188, 5 June 2013, https://doi.org/10.1126/scitranslmed.3005452.
Rock, Kenneth L., et al. “Present yourself! by MHC class I and MHC class II molecules.” Trends in Immunology, vol. 37, no. 11, Nov. 2016, pp. 724–737, https://doi.org/10.1016/j.it.2016.08.010.
Schuldt, Nathaniel J, and Bryce A Binstadt. “Dual TCR T cells: Identity crisis or multitaskers?” The Journal of Immunology, vol. 202, no. 3, 1 Feb. 2019, pp. 637–644, https://doi.org/10.4049/jimmunol.1800904.
Schuldt, Nathaniel J, et al. “Cutting edge: Dual TCRΑ expression poses an autoimmune hazard by limiting regulatory T cell generation.” The Journal of Immunology, vol. 199, no. 1, 1 July 2017, pp. 33–38, https://doi.org/10.4049/jimmunol.1700406.
Vincent, Benjamin G., and Jonathan S. Serody. “One is better than two: TCR pairing and GVHD.” Science Translational Medicine, vol. 5, no. 188, 5 June 2013, https://doi.org/10.1126/scitranslmed.3006431.