February 29, 2024

A New Technique Reveals How Immune Cells Locate Their Targets

Both B and T cells play vital roles in launching an immune reaction. When a T cell experiences its target, it starts proliferating to produce an army of identical cells that can assault infected cells. And B cells that experience their target begin producing antibodies that help hire other components of the immune system to clear the infection.
Birnbaums laboratory is now working on adjusting the same viruses to deliver engineered genes to target cells. In that case, the viruses would bring not only a targeting molecule however also a novel gene that would be included specifically into cells that have the right target.

Previous MIT college student Connor Dobson is the lead author of the paper, which was published on April 8th, 2022, in Nature Methods.
An easy screen for an intricate system
Both B and T cells play critical functions in introducing an immune response. When a T cell experiences its target, it begins proliferating to produce an army of similar cells that can assault infected cells. And B cells that experience their target begin producing antibodies that assist hire other elements of the body immune system to clear the infection.
Researchers who study the body immune system have several tools to assist them recognize particular antigen-immune cell interactions. However, these tools normally just enable for the study of a big swimming pool of antigens exposed to one B or T cell, or a large swimming pool of immune cells encountering a small number of antigens.
” In your body, you have millions of unique T cells, and they might acknowledge billions of possible antigens. All of the tools that have actually been established to this point are really developed to look at one side of that diversity at a time,” Birnbaum states.
The MIT group set out to create a new tool that would let them screen huge libraries of both antigens and immune cells at the very same time, allowing them to choose any specific interactions within the large world of possibilities.
To produce a basic method to screen so lots of possible interactions, the scientists crafted a specialized form of a lentivirus, a type of virus that researchers often utilize to deliver genes since it can integrate pieces of DNA into host cells. These infections have an envelope protein called VSV-G that can bind to receptors on the surface of numerous kinds of human cells, including immune cells, and infect them.
For this study, the researchers customized the VSV-G protein so that it can not infect a cell on its own, instead depending on an antigen of the scientists picking. This customized variation of VSV-G can just help the lentivirus get into a cell if the paired antigen binds to a human B or T-cell receptor that recognizes the antigen.
When the infection goes into, it integrates itself into the host cells genome. By sequencing the genome of all the cells in the sample, the researchers can find both the antigen revealed by the infection that contaminated the cell and the series of the T or B-cell receptor that enabled it to get in.
” In this way, we can utilize viral infection itself as a method to match up and then recognize antigen-immune cell parings,” Birnbaum says.
Interactions recognized
To demonstrate the accuracy of their strategy, the scientists produced a swimming pool of infections with antigens from 100 various infections, including influenza, cytomegalovirus, and Epstein-Barr infection. They screened these viruses against about 400,000 T cells and showed that the strategy might properly select out antigen-T-cell receptor pairings that had actually been previously identified.
The scientists also evaluated 2 different B-cell receptors against 43 antigens, including antigens from HIV and the spike protein of SARS-CoV-2.
In future research studies, Birnbaum wants to evaluate thousands of antigens against B and T cell populations. “Our perfect would be to evaluate entire infections or households of infections, to be able to get a readout of your whole immune system in one experiment,” he states.
In one research study that is now continuous, Birnbaums laboratory is dealing with scientists at the Ragon Institute of MGH, MIT, and Harvard to study how different peoples body immune systems react to viruses such as HIV and SARS-CoV-2. Such studies could help to expose why some individuals naturally fight off particular viruses better than others, and potentially lead to the advancement of more efficient vaccines.
The scientists picture that this innovation could likewise have other usages. Birnbaums lab is now dealing with adapting the exact same viruses to provide engineered genes to target cells. Because case, the viruses would carry not just a targeting molecule but also a novel gene that would be integrated exclusively into cells that have the right target. This could provide a method to selectively provide genes that promote cell death into cancer cells, for example.
” We developed this tool to try to find antigens, but theres absolutely nothing particularly unique about antigens,” Birnbaum states. “You could potentially utilize it to go into specific cells in order to do gene modifications for cell and gene therapy.”
The research study was funded by the Koch Institute Frontier Award program, the Packard Foundation, the Damon Runyon Cancer Research Foundation, the Michelson Medical Research Foundation, Pfizer, Inc., the Department of Defense, the National Institutes of Health, a National Science Foundation Graduate Research Fellowship, a Siebel Scholarship, a Canadian Institutes of Health Research Doctoral Foreign Study Award, a graduate fellowship from the Ludwig Center at MIT, a Medical Scientist Training Program grant from the National Institute of General Medical Sciences, a Technology Impact Award from the Cancer Research Institute, the Pew-Stewart Scholarship program, and the Koch Institute Support (core) Grant from the National Cancer Institute.
Recommendation: “Antigen identification and high-throughput interaction mapping by reprogramming viral entry” by Connor S. Dobson, Anna N. Reich, Stephanie Gaglione, Blake E. Smith, Ellen J. Kim, Jiayi Dong, Larance Ronsard, Vintus Okonkwo, Daniel Lingwood, Michael Dougan, Stephanie K. Dougan, and Michael E. Birnbaum, 8 April 2022, Nature Methods.DOI: 10.1038/ s41592-022-01436-z.

MIT biological engineers have actually devised a method to carry out large-scale screens of how T cells such as this one acknowledge specific pathogens, such as the HIV viruses (yellow) show in this image. Credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases/NIH
MIT biological engineers have actually established a basic way to determine B or T cells that engage with bacterial or viral proteins.
The body has millions of special B and T cells that roam the body, looking for microbial intruders. These immune cells capability to acknowledge damaging microbes is critical to effectively eradicating infection.
MIT biological engineers have actually now devised a speculative tool that enables them to precisely select out interactions between a specific immune cell and its target antigen. The new technique, which utilizes crafted infections to provide several antigens to big populations of immune cells, might allow large-scale screens of such interactions.
” This strategy leads the way to understand resistance much closer to how the immune system itself in fact works, will assist researchers understand complicated immune recognition in a range of illness, and might accelerate the development of more reliable vaccines and immunotherapies,” says Michael Birnbaum, an associate teacher of biological engineering at MIT, a member of MITs Koch Institute for Integrative Cancer Research, and the senior author of the research study.