The Chemistry of Cytotoxic T Cells

Introduction

A cytotoxic t cell (CTL) is a type of T cell; T cells are in turn classified as lymphocytes, which are a subtype of leukocytes (white blood cells). The main job of CTLs is to kill infected, cancerous, or damaged cells. These actions play a central role in cell mediated immunity, an immune response critical to the function of the adaptive immune system. The job of the cell mediated response is kill pathogens by destroying any cells they have infected. CTLs are one of the main types of cells responsible for destroying these cells. CTLs are referred to as being part of the adaptive or specific immune system because CTLs only destroy cells presenting the specific antigen they are designed to recognize, and also because they have the power to “remember” the experience so it can respond quicker and more effectively if the disease is to enter the body again.  


I chose to study CTLs because I am interested in how the immune system and its separate parts function. CTLs are an extremely important part of my life because they help me survive every day. Without them, my immune system couldn’t function and I would have to severely restrict my activities to make sure I would never come in contact with a disease.


Composition of ...

  • cell membrane

  • cytoplasm

  • nucleus

  • various organelles

  • T cell receptor (TCR)

  • lysosomes

    • granzymes a,b,h,k,m

    • perforin


Main Chemicals, Compounds, Components

  • Granzymes A and B (GzmA and GzmB): GzmA and GzmB are two of the five types of granzymes found in the human body. Granzymes A and B are the most common and most extensively studied. Granzymes (granular enzymes) are serine proteases (enzymes that cleave peptide bonds). They are stored in granules (small secretory vesicles) in the cytoplasms of CTLs and Natural Killer cells. When the the CTL binds to the target cell using its TCR, the vesicle containing the granzymes is released through exocytosis. After entering the target cell the different granzymes induce apoptosis (programmed cell death). Granzyme B activates caspase (cysteine-aspartic protease) 3 and caspase 7, which then cleave important cellular substrates. Without these the cell cannot function, and subsequently dies. Unlike GzmB, GzmA induces a caspase independent form of apoptosis that disrupts the metabolism of the mitochondria, triggering a reaction that causes the endoplasmic reticulum associated SET complex to activate DNA damage. GzmA also causes the destruction of essential nuclear proteins, among them proteins involved in DNA damage repair. The reason there are multiple granzymes for the same job is because every so often a cell will be protected against one or more methods of destruction.

  • Perforin: Perforin is a cytolytic protein found in the granules of CTLs and Natural Killer cells along with granzymes. When a CTL binds to the target cell and releases its granules, the perforin forms pores in the target cell’s membrane. This causes an influx of calcium into the cell. This chemical imbalance triggers membrane repair processes, inadvertently bring the granzymes into the cell.

Chemistry's Role

Chemistry is an integral part of CTLs creation and function. As discussed in the background section below, CTLs are created after helper T cells are stimulated during antigen presentation. During antigen presentation, the phagocyte involved produces a chemical called interleukin 1 which makes the helper T cell produce interleukin 2 which causes that same cell to start rapidly dividing, producing CTLs (this process is known as autocrine signalling). Chemistry is also involved in the function of CTLs. Granzymes and the protein Perforin are both considered chemicals. As discussed in the section above, the granzymes sent from the CTL into the target cell, where through various processes that are not yet fully understood, trigger apoptosis. The two best studied and understood Granzymes are Granzyme A (GzmA) and Granzyme B (GzmB). GzmA kills cells by disrupting the metabolism of mitochondria, which initiates one of the target cell’s death pathways. GzmB activates caspases 3 and 7, which go on to start a chain reaction that ends with the cell’s death. Perforin creates small pores in the membrane of the target cell which results in a chemical imbalance in the cell. This causes the cell to begin its membrane repair processes which suck the granzymes into the cell.

Background Research

The immune system contains three lines of defense. The first line of defense consists of physical and chemical barriers such as skin, mucous membranes, gastric acid, etc. The second line of defense consists of the innate immune system. The innate or nonspecific immune  system comes into effect after a disease has entered your body. It focuses on killing pathogens while they are outside of your cells, and has no ability to retain information about or adapt to any pathogens it defeats. The third line of defense is the adaptive or specific immune system. The adaptive immune system is responsible for defeating pathogens after they have entered cells and passed beyond the reach of the innate immune system. T cells and B cells play a very large role in the adaptive immune system because they deeply involved in the the adaptive immune system’s ability to retain information about past pathogens and to mount a faster and more effective response when pathogens reappear. There are many types of T cells such as effector T cells, helper T cells, and memory T cells. Effector T cells, which are T cells that actively defend the body, include cytotoxic T cells. After a phagocyte consumes an antigen, it travels to one of the nearest peripheral lymphatic organs. There the phagocyte finds a helper T cell and begins antigen presentation, a process in which the phagocyte displays fragments of the consumed antigen on its membrane for the helper T cell to examine. After antigen presentation, the helper T cell will begin dividing rapidly. The new T cells will differentiate into effector and memory T cells. There are different varieties of T cells, one of which are cytotoxic T cells. These will then go out and find more cells infected with the same virus and kill them.

Resources

Resources

http://www.austincc.edu/apreview/EmphasisItems/Inflammatoryresponse.html

  • chemical barriers and of the first line of defense of the immune system:lysozyme, saliva, gastric juice, skin acidity, sebum

  • how these chemical barriers work

https://www.nlm.nih.gov/medlineplus/ency/article/000821.htm

  • information about how innate humoral immunity works

  • information about how the inflammatory response works

http://www.nlm.nih.gov/pubmed/26490004

  • information about how the immune system is directed w/chemical compounds

  • discusses the role agonists of immune cell receptors

  • article focuses on agonists of toll-like receptors (TLRs) and the molecular characteristics that affect receptors binding and activation and how it relates to immune stimulus

www.uic.edu/classes/bios/bios100/lecturesf04am/lect23.htm

  • discusses the lines of defense in the immune system

  • lists many of the main cells involved

  • has information on the cascade effect

  • hs information on chemokines and interleukins

  • has information on many of the cells involved

http://www.britannica.com/science/immune-system

  • discusses the innate and adaptive immune system

  • details the workings of the immune system

http://www.microsite.garlandscience.com/textbooks/0815365144/site/content/lecture_notes/chapter_15.pdf

  • more information about the innate vs. adaptive immune system

  • information about different types of chemical barriers

http://www.health.howstuffworks.com/human-body/systems/immune/immune-system3.htm

  • discusses the different purposes of the immune system

  • discusses the different lines of defense

http://www.ck12.org/biology/Barriers-to-Pathogens/studyguide/Immune-System-Part-I-Study-Guide/

  • discusses different aspects of the immune systems lines of defense

  • discusses humoral response

  • discusses the cell mediated response

  • information about the lymphatic system

http://www.youtube.com/watch?v=CeVtPDjJBPU

  • Discusses the many different types and functions of leukocytes

http://www.jcs.biologists.org/content/119/24/5011

  • lists the number and type of granzymes in the human body

  • has some information on perforin

http://www.en.wikepedia.org/wiki/lymphocyte

  • general information on lymphocytes

http://www.en.wikipedia.org/wiki/granzyme

  • general information about granzymes

  • how granzymes are used

  • how some granzymes trigger apoptosis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3921602

  • how granzymes transfer from the CTL to the target cell

  • where granzymes are stored in the CTL

  • how many granzymes are in the human body

http://www.ncbi.nlm.nih.gov/pubmed/15780992

  • how GzmA induces apoptosis

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC29050780

  • how GzmA induces apoptosis

  • miscellaneous information about GzmA

http://www.users.rcn.com/jkimball.ma.ultranet/BiologyPages/C/CTL.html

  • general information about CTLs

  • Properties of CTLs

  • Mechanisms of Killing

http://www.ncbi.nlm.nih.gov/books/NBK27149

  • general properties of armed effector T cells

  • general information about armed effector T cells

http://www.wikipedia.org/wiki/Perforin

  • extensive information on perforin

http://www.medical-dictionary.thefreedictionary.com/perforin

  • short explanations of perforin’s effect on membranes

http://www.nature.com/icb/journal/v84/n1/full/icb200610a.html

  • discusses perforin

About the Author

Elena Borges is a junior at Billings Senior High. She has run cross country for three years, and played tennis for two. She is also involved in Interact Club, Arts Without Boundaries Mentoring Program, and Flag Corps. She enjoys skiing, caving, and backpacking in her free time. After graduation, she hopes to attend University of Arizona, where she intends to study epidemiology.


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