Dr. Tak Wah Mak and the Discovery of T-Cell Receptor

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Dr. Tak Wah Mak
Dr. Tak Wah Mak  DON DIXON/ASYLUM ARTISTS

Dr. Tak Wah Mak and the Discovery of T-Cell Receptor

Tak Mak was raised in Hong Kong and went to a religious school. His parents wanted him to become a doctor, but he had other ideas such as pursuing history, math, biology, and chemistry. Mak’s family migrated to the United States in the 1960s. Mak wanted to study at the University of California Berkeley but his parents discouraged him to go there due to the institution’s antiwar activities. He ended up going to the University of Wisconsin where he initially pursued chemical engineering but shifted to graduate with a major in biochemistry. After 2 more years, Mak graduated Master’s in biophysics. He moved to Canada and pursued his doctorate degree at the University of Alberta.

While attending the University of Wisconsin, Mak met three persons who he thinks helped his career. Roland Rueckert is a virologist and a professor at the institution’s biochemistry department. Mak worked in Roland’s lab as a dishwasher that pays $1.25 per hour. He later asked for more work and Roland gave him the opportunity to help in research experiments. Mak said that working in Roland’s research experiments was the start of his scientific career.

Robert was studying picornaviruses specifically in replication and assembly. Mak coauthored Robert’s paper that is published in Intervirology. The paper involved the use of sodium metaperiodate in concentrations at a micromolar scale which typified Robert’s approach to science and made a huge impression on Mak. With Robert’s works, Mak learned the systematic approach and precision in scientific research as well as discipline and organizing research experiments.

Mak pursued his postdoctoral training at the Ontario Cancer Institute where he continued to be a senior scientific staff. Mak worked in the laboratories of Ernest McCulloch and James Till, discoverers of hematopoietic stem cells. Ernest thought Mak how to challenge dogma and not to believe everything that was written. If Mak raised a question on a theory, Ernest would ask for several speculations. Mak’s experience with Ernest is like a new door opened and that he learned the advantages of a careful, systematical approach to exploring the unknown.

One of Mak’s research involved cloning and sequencing mRNA specific for T cells. They found that the mRNA was transcribed in T lymphoblasts, thymocytes, phytohaemagglutinin-stimulated T lymphocytes. The protein from the cDNA sequence was found to have a molecular weight of 34,938 and shows high similarity with the variable, joining, and constant regions of the light chains in mammalian immunoglobulin. They also found that the relative positions of the cysteine residues are much alike with the light chains of immunoglobulin from humans and murine. Mak’s team proposed that the cDNA clone may be associated with a subunit of the human T-cell receptor. Mak’s research identified a very important feature of modern immunology. This relates to our new understanding of immunology because it gives information on how and where T-cell receptor-specific mRNA is transcribed. Without Mak’s research, we may not be able to know that T-cell receptors are highly similar to immunoglobulin.

Another of Mak’s research involved the study of lymphoproliferative disorders in CTLA-4 deficient mice. In 1995, the role of CTLA-4 receptor in regulating the activation of T-cell has been controversial. In this study, they observed an accumulation of activated T cells in the spleen and lymph nodes in mice with CTLA-4 deficiency. They also observed that the activated T cells invade the lung, heart, pancreas, and liver tissues. The test shows serum immunoglobulin level is increased. In every case, the mice died at the age of 3 to 4 weeks. It was observed that the CTLA-4 deficient T cells were prone to apoptosis induced by Fas receptor cross-links and by gamma irradiation. They conclude that CTLA-4 may be a negative regulator in the activation of T-cells and is important for the control of homeostasis in lymphocytes. This relates to our new understanding of immunology because it gives additional information about the CTLA-4 receptors and how it contributes to the prognosis of an immune disorder. We have studied antigen presentation, activation, and proliferation of T cells however, we lack the knowledge of regulating these processes. With Mak’s research, we have learned about CTLA-4 receptor and its correlation with the regulation of T cell activation by controlling the apoptotic pathways.

One drug that can be related to Mak’s research is called abatacept, also known as CTLA-4-Ig, which is a treatment for autoimmune diseases. The drug imitates the function of CTLA-4 protein and decreases the activity of the immune system. Although the effectiveness of abatacept for treating CTLA-4 requires further study, abatacept has been used to treat autoimmune diseases such as rheumatoid arthritis. Abatacept is a soluble, humanized fusion protein that contains CTLA-4 extracellular domain and the Fc part of IgG1. It binds to the CD80 and CD86 of antigen-presenting cells and does not allow the binding of CD28 receptor of T cells. Abatacept also acts on other cells such as regulatory T cells, osteoclasts, monocytes, macrophages, and B cells.

Sources:

Viegas, J. (2011). Profile of Tak Wah Mak. PNAS 108 (48) 19124-19126. https://www.pnas.org/content/108/48/19124.full

Yanagi, Y., Yoshikai, Y., Leggett, K. et al. A human T cell-specific cDNA clone encodes a protein having extensive homology to immunoglobulin chains. Nature 308, 145–149 (1984). https://www.nature.com/articles/308145a0

Waterhouse, P., et. Al. (1995). Lymphoproliferative Disorders with Early Lethality in Mice Deficient in Ctla-4. Science Vol. 270, Issue 5238, pp. 985-988 DOI: 10.1126/science.270.5238.985. https://science.sciencemag.org/content/270/5238/985

National Institute of Allergy and Infectious Diseases. (2019). CTLA-4 Deficiency. https://www.niaid.nih.gov/diseases-conditions/ctla4-deficiency

Bonelli, M., & Scheinecker, C. (2018). How does abatacept really work in rheumatoid arthritis?. Current opinion in rheumatology, 30(3), 295–300. https://pubmed.ncbi.nlm.nih.gov/29401118

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