A Possible Evolution of the Current Influenza Vaccine

Based on the study by van Wilgenburg et al. (2018): Mait cells contribute to protection against lethal influenza infection in vivo.

            Influenza, commonly known as “the flu,” refers to a wide umbrella of similarly constructed viruses that infects between 3-5 million people and kills up to 650,000 people annually.¹ When people become infected by different types of foreign organisms, the immune system attempts to respond specifically to eliminate that pathogen, or foreign organism. There is an initial response by different types of non-specific immune cells that try to rid the body of the pathogen. If the initial response fails, there is a more specific response by T and B cells to better aid the body. It has recently been discovered that mucosal-associated invariant T (MAIT) cells act somewhere between being non-specific and specific. MAIT cells reside in the surfaces that produce mucus, such as the lungs, nasal cavity, and gut, and have a receptor that varies slightly such that it recognizes a broad class of proteins. MAIT cells are activated in response to specific viral infections, rather than just bacterial infections as was previously understood.⁵  MAIT cells are a subset of T cells that express a semi-invariant α/β T cell receptor (TCR) that recognizes the highly conserved viral riboflavin protein which is common in many viruses, but structurally different in humans. This T cell receptor binds to riboflavin present on MR1, the protein on the surface of the infected cell that allows the immune system to recognize the presence of a virus and mount a response. Due to the semi-invariant receptor and the recognition of a conserved structure, MAIT cells function in the innate immune response early in infection. They are able to recognize the pathogen to be viral, but may not recognize what type of virus is infecting the body. This allows the MAIT cells to respond in a partially specific capacity. It has also been found that MAIT cells can be activated by binding other proteins than just MR1. Cytokines, which are messenger molecules, such as interleukin-18 (IL-18) in concert with either IL-12, IL-15, or interferon α or β (IFN α or β), also cause the MAIT cells to respond. MAIT cells will produce molecules called IFNγ and granzyme B. IFNγ and granzyme B are both death-inducing signals for infected cells and cause an infected cell to die. Van Wilgenburg et al. (2018) demonstrated that MAIT cells accumulate at the lungs during infection with influenza A (the most common form of human influenza) and can be activated via cytokines without direct interaction of the TCR with MR1.

            The research team infected mice with a strain of type A influenza virus that causes mouse pneumonia to investigate the action of MAIT cells. They found that after 5 days, the levels of pulmonary (lung) MAIT cells drastically increased, as well as outnumbered adaptive, specific T cells (CD4⁺ and CD8⁺). The researchers used strains deficient in each cytokine (IL-18, IL-12, IL-15, and IFNα) or MR1 to investigate their different roles in the activation of MAIT cells. Interestingly, depletion of IL-18 was the only experimental manipulation that decreased MAIT cell accumulation after influenza A virus infection. This implies that IL-18 is necessary to bring MAIT cells to the lungs and other mucosal surfaces. Although IL-18 reduced the number of MAIT cells, depletion of IL-15, IL-18, IFNα, and most of all IL-12, caused decreased activation of MAIT cells. The difference between the two conditions is that MAIT cells were still present in the pulmonary mucosa after IL-12, IL-15 and IFNα depletion, but were not actively fighting the virus through secretion of IFNγ and granzyme B. The research team was also able to observe that the activation of MAIT cells could occur completely independently of MR1 presentation of riboflavin because mice with genetically depleted MR1 still showed increased levels of pulmonary MAIT cells. Mice genetically deficient in MR1 with transferred MAIT cells were still able to activate these MAIT cells in the presence of the proper cytokines. These results indicate that in the absence of MR1, activation of MAIT cells is driven by IL-18 and IL-12, but is also influenced by IL-15 and IFNα. In IL-18 deficiency, there will be decreased MAIT responses to influenza A virus due to reduced numbers, but as long as IL-12 is present, there will still be some response. Without IL-12, there is very little activation of, and response by, MAIT cells.

Figure 1: a. Demonstrates a significant decrease of pulmonary MAIT cell accumulation after IL-18 depletion. b. Demonstrates decreased activated MAIT cells after depletion of IL-12, IL-18, IL-15, and IFNα.

After determining that MAIT cells were, in fact, activated by cytokines in the pulmonary mucosa of influenza infected mice, the researchers continued research to determine whether MAIT cells were beneficial or detrimental to the host. After induction of viral infection in MR1 (MAIT) deficient mice, these mice showed greater weight loss and lower survival rates than wildtype, or “normal,” mice exposed to the same virus. These effects were reversed in mice deficient for MR1 that had MAIT cells transferred to them via intravenous (IV) injection. Additionally, MR1 deficient-mice had reduced numbers of macrophages and T cells at the pulmonary mucosa, demonstrating an overall decreased immune response in the absence of MAIT cells. There were also decreased numbers of specific T cells in other areas of the body in MAIT deficient mice, indicating that they may play a role in activation of an immune response to the specific pathogen. Together, these results demonstrate that MAIT cells play a protective role in the host as both a primary form of defense at sites of infection, but also as a potential link between the innate (non-specific) and adaptive (specific) immune responses after influenza infection. To further study the role of MAIT cells, the researchers used a separate group of mice that received a less intense strain of influenza and found similar results as their previous experiments.

Figure 2: d. Demonstrates that there are decreased numbers of pulmonary macrophages in MAIT deficient mice. e. Demonstrates that there are decreased numbers of pulmonary T cells (specific immune responses) in MAIT deficient mice. 

           Overall, this paper demonstrates that MAIT cells are protective in mice, indicating that they likely function similarly in humans. The protective effects observed are surprising considering mice have a low proportion of MAIT cells compared with humans.¹⁶ The determination that pulmonary MAIT cells are important to immune responses to influenza is extremely important because they have been found to be reduced in individuals taking inhaled or oral corticosteroids (immunosuppressants) especially for asthma¹⁶ and chronic obstructive pulmonary disease (COPD).¹⁷ This leaves these individuals more susceptible to developing severe cases of influenza. The determination of the specific cytokines activating MAIT cells will allow for more targeted therapeutic treatments to individuals with certain deficiencies in the future. Additionally, MAIT cell activation occurs independently of T cell receptors, as demonstrated through depletion of MR1, meaning they can potentially be a targeted cell in the creation of a “universal flu vaccine.”  Current flu vaccines rely on the specificity of the virus binding to T cell receptors to induce protective effects. If MAIT cells can be targeted for activation by vaccines, this would be an important step towards developing a universal flu vaccine since they are already not antigen specific. Due to their semi-specificity, MAIT cells would be ideal to create a memory response to multiple different flu strains. Future studies should be dedicated to determining the ability to incorporate MAIT-activating ligands (molecules) in vaccines as a possible adjuvant to increase adaptive immune responses. This study clearly demonstrates that MAITs play an early protective role against influenza viruses. Future studies should focus on determining the mechanisms of MAIT cell activity that specifically help link the innate and the adaptive immune responses. Specific mechanisms that demonstrate how T cells increase after MAIT activation would give insight into the aforementioned question. If the pathways that link the innate and adaptive responses via MAIT are characterized, there would potentially be more therapeutic targets to decrease intensity of influenza infections. Rather than just targeting MAIT-cell activation before infection, as a vaccine would do, by increasing MAIT activation at the earliest signs of influenza infection, a faster adaptive response could be mounted and individuals may recover more quickly. Although there are still many unknowns, MAIT cells should be further investigated due to their unique connecting role between the early and late immune responses and their semi-specificity.

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