In this episode, Naïve T Cell patrols the body to find and kill influenza-infected cells. However, he gets easily scared by the influenza-infected cells that are portrayed as zombies. He is paralysed as the other White Blood Cells kill the influenza-infected cells and gets berated by Killer T Cell for not joining in the fight. Eventually, Naïve T Cell runs away from the battlefield and meets Dendritic Cell. Dendritic Cell encourages Naïve T Cell by explaining how every killer T cell went through the same experiences as him in the past and how every white blood cell is supporting him. These facts allowed Naïve T Cell to evolve into Effector T Cell who can effectively kill influenza-infected cells, ending the infection.

How do naïve T cells evolve into effector T cells in the human body and how do dendritic cells (DCs) contribute to this process? Join us as we unpack what the influenza virus is and how T cells are activated.

What is influenza?

Schematic	Microscopic	Anime

Influenza is a respiratory infection caused by the influenza virus. The virus possesses a lipid membrane that is studded with surface proteins such as haemagglutinin (HA) and neuraminidase (NA). Inside the virus are viral RNA segments that are covered with viral proteins to form ribonucleoprotein complexes (vRNPs). Influenza comes in four types: A, B, C and D. Of these, influenza A and B are the most important as they can infect humans, particularly during winter. This produces symptoms such as cough, fever, headache and muscle pain but can worsen to respiratory failure that could lead to death. In addition, influenza A can also infect other warm-blooded animals such as birds and pigs. If these influenza viruses acquire the ability to efficiently infect humans, they can cause pandemics associated with widespread infection and death.

Did you know? Influenza viruses are subtyped by two surface proteins: haemagglutinin and neuraminidase. Human influenza strains are commonly H1N1 and H3N2 while avian influenza strains are commonly H5N1 and H7N9.

Viruses can only replicate by infecting and taking over cells. The influenza virus is no exception, infecting respiratory epithelial cells in the nose and lungs. They replicate within these cells by taking over the cell’s machinery to produce viral RNA and proteins. This is represented by zombies in the anime where host cells only live to generate new influenza viruses. New vRNPs are made inside the cell which are packaged underneath buds of the cell membrane studded with viral surface proteins. These buds are eventually cut off from the cell, freeing influenza viruses to infect other cells.

Many different cells respond to influenza infection. Respiratory epithelial cells secrete various chemicals such as lectins and anti-microbial proteins that bind to influenza viruses to prevent them infecting cells. Respiratory epithelial cells can also sense when they are infected by influenza. Infected cells release chemical mediators called interferons that travel to nearby cells to enhance their protection against influenza. The innate immune system is also activated to limit the spread of influenza. Neutrophils, being the first to arrive in the infected lung, phagocytose and degrade influenza viruses. Macrophages arrive later to phagocytose influenza viruses and cell debris as well as secrete cytokines and chemokines to recruit and activate other white blood cells. Later in infection, antibodies target and neutralise surface proteins in influenza viruses to prevent them from infecting other cells as well as tag them for phagocytosis and degradation by white blood cells.

T cell activation

Talking about DCs

DCs are innate immune cells that process and present antigens to T cells. Immature DCs are normally present in the healthy lung to sample the external environment in the airways. However, during influenza infection, DCs engulf influenza viruses or influenza-infected cells, detecting components of influenza to become activated. Activated DCs migrate to the draining lymph nodes outside the lung, maturing along the way so that they can present antigens to T cells. DCs also break down influenza antigens into peptide fragments called epitopes that are loaded on MHC complexes and presented to naïve T cells. There are two types of MHC complexes: MHC class I complexes present epitopes to naïve CD8⁺ T cells which become killer T cells while MHC class II complexes present epitopes to naïve CD4⁺ T cells which become helper T cells.

About T cells

T cells are lymphocytes that participate in the adaptive immune response against influenza. T cells develop in the thymus where they generate a T cell receptor (TCR) that binds to a specific epitope-MHC complex. They express either CD4 or CD8 which marks them as an eventual helper or killer T cell respectively. Once they leave the thymus, T cells circulate around the body and visit the spleen and lymph nodes to find the epitope-MHC complex that fits their TCR.

Analogous to the encouragement Dendritic Cell gave to Naïve T Cell in the anime, T cells typically require two signals to be activated which are provided by activated DCs. Signal 1 is associated with the TCR on the T cell recognising the epitope-MHC complex on DCs. Once this interaction is stabilised by CD4 or CD8 and the surrounding adhesion molecules, intracellular signalling pathways inside the T cell are activated which are necessary but not sufficient for T cell activation. This also requires secondary or co-stimulatory signals provided by activated DCs which constitute signal 2. Secondary signals act to promote T cell proliferation (via CD28 on T cells interacting with CD80/86 on DCs) and survival (via OX40 and 4-1BB on activated T cells binding to their respective ligands on activated DCs).

Did you know? If the T cell interacts with the epitope-MHC complex without costimulatory signals, the T cell will not activate and will not respond to any future stimuli. This stops activation of T cells that react to antigens from its own cells to attack its own organs and tissues (an undesirable event!), causing autoimmune disease.

Activated T cells emerge out of the draining lymph nodes and migrate to the infected lung. Naïve CD4⁺ T cells become helper T cells while naïve CD8⁺ T cells become killer T cells. Helper T cells secrete a variety of cytokines to coordinate immune activity, particularly in activating B cells to promote antibody responses. Helper T cells also interact with macrophages to become more efficient killers of influenza and influenza-infected cells. In contrast, killer T cells kill influenza-infected cells in two ways. It can either directly interact with infected cells via its death receptors or it can release enzymes (called granzymes) and perforin to puncture and kill infected cells.

Conclusion

Influenza viruses infect epithelial cells in the nose and lungs to not only replicate but also cause respiratory infection. The body has various ways to inhibit replication of the influenza virus and eliminate infection. Among these, T cells play an important role. Naïve T cells are activated by DCs in the draining lymph nodes where they evolve into helper or killer T cells. Along with antibodies, these T cells contribute to the adaptive immune system, clearing the influenza virus and eliminating influenza-infected cells to end infection.   

Join us next time as we look at two different pathogens that cause food poisoning and how different white blood cells are involved in eliminating them. See you then!