MIT biological engineers have developed a simple way to identify B or T cells that interact with viral or bacterial proteins.
The human body has millions of unique B and T cells that roam the body, looking for microbial invaders. These immune cells’ ability to recognize harmful microbes is critical to successfully fighting infection.
MIT biological engineers have now devised an experimental tool to precisely pick out interactions between a particular immune cell and its target antigen. The new technique, which uses engineered viruses to present many different antigens to vast populations of immune cells, could allow large-scale screens of such interactions.
Caption: MIT biological engineers have devised a way to perform large-scale screens of how T cells such as this one recognize specific pathogens, such as the HIV viruses (yellow) shown in this image. Image credit: Seth Pincus, Elizabeth Fischer and Austin Athman, National Institute of Allergy and Infectious Diseases/NIH
“This technique leads the way to understand immunity much closer to how the immune system itself works, will help researchers make sense of complex immune recognition in a variety of diseases, and could accelerate the development of more effective vaccines and immunotherapies,” says Michael Birnbaum, an associate professor of biological engineering at MIT, a member of MIT’s Koch Institute for Integrative Cancer Research, and the senior author of the study.
Former MIT graduate student Connor Dobson is the paper's lead author, which appears in Nature Methods.
A simple screen for a complex system
Both B and T cells play critical roles in launching an immune response. When a T cell encounters its target, it increases to produce an army of identical cells that can attack infected cells. And B cells that meet their target begin producing antibodies that help recruit other components of the immune system to clear the infection.
Scientists who study the immune system have several tools to help them identify specific antigen-immune cell interactions. However, these tools generally only allow the study of a large pool of antigens exposed to one B or T cell or an extensive collection of immune cells encountering a small number of antigens.
“In your body, you have millions of individual T cells, and they could recognize billions of possible antigens. All of the tools developed are designed to look at one side of that diversity at a time,” Birnbaum says.
The MIT team set out to design a new tool that would screen vast libraries of both antigens and immune cells simultaneously, allowing them to pick out any specific interactions within the vast realm of possibilities.
To create a simple way to screen so many possible interactions, the researchers engineered a specialized form of a lentivirus, which scientists often use to deliver genes because it can integrate pieces of DNA into host cells. These viruses have an envelope protein called VSV-G that can bind to receptors on the surface of many human cells, including immune cells, and infect them.
For this study, the researchers modified the VSV-G protein so that it cannot infect a cell on its own instead of relying on an antigen of the researchers’ choosing. This modified version of VSV-G can only help the lentivirus get into a cell if the paired antigen binds to a human B or T-cell receptor that recognizes the antigen.
Once the virus enters, it integrates itself into the host cell’s genome. Therefore, by sequencing the genome of all the cells in the sample, the researchers can discover both the antigen expressed by the virus that infected the cell and the sequence of the T or B-cell receptor that allowed it to enter.
“In this way, we can use viral infection itself to match up and then identify antigen-immune cell parings,” Birnbaum says.
Interactions identified
To demonstrate the accuracy of their technique, the researchers created a pool of viruses with antigens from 100 different viruses, including influenza, cytomegalovirus, and Epstein-Barr virus. They screened these viruses against about 400,000 T cells and showed that the technique could correctly pick out antigen-T-cell receptor pairings that had been previously identified.
The researchers also screened two different B-cell receptors against 43 antigens, including antigens from HIV and the spike protein of SARS-CoV-2.
Birnbaum hopes to screen thousands of antigens against B and T cell populations in future studies. “Our ideal would be to screen entire viruses or families of viruses, to be able to get a readout of your entire immune system in one experiment,” he says.
In one study that is now ongoing, Birnbaum’s lab is working with researchers at the Ragon Institute of MGH, MIT, and Harvard to study how different people’s immune systems respond to viruses such as HIV and SARS-CoV-2. Such studies could help to reveal why some people naturally fight off certain viruses better than others and potentially lead to the development of more effective vaccines.
The researchers envision that this technology could also have other uses. Birnbaum’s lab is now working on adapting the same viruses to deliver engineered genes to target cells. In that case, the viruses would carry a targeting molecule and a novel gene that would be incorporated exclusively into cells that have the right target. For example, this could offer a way to deliver genes that promote cell death into cancer cells selectively.
“We built this tool to look for antigens, but there's nothing extraordinary about antigens,” Birnbaum says. “You could potentially use it to go into specific cells to do cell and gene therapy gene modifications.”
Written by Anne Trafton