Ion Channels in T cells— Channeling a New Research Era?

Reading time: 5 minutes

Christina Niavi

Our human body has amazing defense mechanisms. The organism defense is like the army, with a first line of defense against any kind of threat and, a second defense, more specialized to each threat. Specialized defense soldiers, called CD8 T cells, are equipped with killing machineries to eradicate tumors and pathogens. Imagine, though, a fight (chronic infection/cancer) that lasts so long that the soldiers become exhausted and cannot fight anymore. This is where scientists come in! Research studies aim to boost those CD8 T cells to fight again and last longer in the war. Laboratories all over the world try to come up with new strategies to aid those soldiers. Despite the progress of those studies and their promising results, no one has yet achieved the desired goal; the eradication of infection/cancer. A few strategic approaches include combinations of drugs or other molecules with already used cancer immunotherapy methods such as chemo- or radiotherapy. Other scientists try to use natural or artificial substances to augment the therapeutic efficacy. Here, we will investigate an underdog of science, at least in the immunological setting; an underdog that could become a protagonist! And the name of this is… *drumroll* ion channels!

-What are ion channels?

-Ion channels are small proteins forming pores in cellular membranes that allow ions to pass through, in and out of the cell.

-So, small pores on the cell membrane. So what? No wonder there is not much interest in them.

– Wait! There is more! They are not just holes on a membrane! They are there for several reasons! Through the ion flow regulation, action potential is regulated, cell size and several cellular behaviors and functions are regulated too! Ionic balance is important to keep cells alive and functional. If the balance is dysregulated, many problems can occur. Some of them include the production of important proteins, cell motility and adhesion, as well as proliferation capacity. Ionic dysregulation can also lead to cell death.  

         Although ion channels have been the focus of several research studies, mostly in neurology and physiology, little is known in immunology, especially in T cell research. Nevertheless, the studies that do exist show the great therapeutic potential of ion channel manipulation in T cells because ion channels affect many aspects and behaviors of T cells and are druggable.

Let’s explain these pros in more detail.

– What is the ion channels’ role in T cells?

–  There are several studies implicating ion channels in CD8 T cell differentiation. We have already explained that CD8 T cells are specialized soldiers against infection/cancer threat. But even these soldiers can be divided in further subpopulations called differentiation states. Ion regulation and flow affects the differentiation state of CD8 T cells. One of these subpopulations is called CD8 effector T cells. These are the fighters going straight to the front line as soon as CD8 T cell troops are called to the battlefield. Another group contains memory CD8 T cells. As their name indicates, these cells have the capacity to remember. These cells have records of the enemy they encountered before about the enemy’s appearance, defense strategies and so on, and are prepared to immediately take action if the same enemy ever strikes back after their previous defeat. Our organisms have memory T cell groups specialized for each previous encountered threat. When the fight lasts long the CD8 T cells get tired and end up in this exhausted state. Multiple research studies aim to help those cells to last longer in the battle and have more effector (killing) capacity. Putting all this together, drugs that target ion channels on T cells could change their ionic flow and, thus,  the  aforementioned T cell behaviors and functions. In other words, make the cells stronger, with more efficient killing capacity and able to last longer in the fight. Ionic manipulation could also give researchers the ability of skewing the cell differentiation creating the troops that are most appropriate for the fight, depending the situation. 

-What does druggable mean?

– It means that they are very easily accessible for drugs to target them. Imagine a small drug that gets injected in the body and tries to find its appropriate target in the vast human body with all the cells, tissues and compartments. There are so many obstacles to avoid! How much easier things are when its complementary “LEGO” piece is visible and accessible just there, on the surface of a cell and not somewhere hidden.

         How about we take all this knowledge about the multiple functions of ion channels on cells and put it into therapeutic use? What will happen if we block with drug molecules some of those pores? The ionic balance of the cells will change and, similar to the hormonal balance in people, the cellular behavior will change and some of the above-mentioned cellular functions will be altered! In other words, just by blocking tiny holes on the cell membranes we can manipulate them to work in our favor! How amazing our body is! Even tiny holes on cells have a purpose! Did I hear a woot for science?

Edited by Rachel Cherney

Works Discussed

Cahalan, M. D., & Chandy, K. G. (1997). Ion channels in the immune system as targets for immunosuppression. Current Opinion in Biotechnology, 8(6), 749-756. https://doi.org/https://doi.org/10.1016/S0958-1669(97)80130-9

Chimote, A. A., Hajdu, P., Sfyris, A. M., Gleich, B. N., Wise-Draper, T., Casper, K. A., & Conforti, L. (2017). Kv1.3 Channels Mark Functionally Competent CD8+ Tumor-Infiltrating Lymphocytes in Head and Neck Cancer. Cancer Res, 77(1), 53-61. https://doi.org/10.1158/0008-5472.Can-16-2372

Feske, S. (2007). Calcium signalling in lymphocyte activation and disease. Nat Rev Immunol, 7(9), 690-702. https://doi.org/10.1038/nri2152

Pauken, K. E., & Wherry, E. J. (2015). Overcoming T cell exhaustion in infection and cancer. Trends in Immunology, 36(4), 265-276. https://doi.org/https://doi.org/10.1016/j.it.2015.02.008

Sim, J. H., Kim, K. S., Park, H., Kim, K.-J., Lin, H., Kim, T.-J., Shin, H. M., Kim, G., Lee, D.-S., Park, C.-W., Lee, D. H., Kang, I., Kim, S. J., Cho, C.-H., Doh, J., & Kim, H.-R. (2017). Differentially Expressed Potassium Channels Are Associated with Function of Human Effector Memory CD8+ T Cells [Original Research]. Frontiers in Immunology, 8(859). https://doi.org/10.3389/fimmu.2017.00859

Header image: https://upload.wikimedia.org/wikipedia/commons/b/b5/Ion_channels.png

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