For linguistics enthusiasts, you might find it curious that almost every language uses anatomical metaphors in everyday speech. For example, you may have heard the phrase: “that cost an arm and a leg” or “I’d give up a kidney to [fill in blank].” To those we love we might say, “you are my heart.” In Persian, “jigare mani” serves a similar function as “my love” and literally translates to “you are my liver.”
Now, as far I know, we never seem to offer up our lymph nodes or our spleen. Despite gaining a wealth of insight regarding their function over the last hundred years, they still haven’t made it onto the cultural radar. These tissues, known as secondary lymphoid organs (SLOs), are very important to our response to pathogens.
A neat feature of SLOs is that not only do they play a vital role in the immune response, they undergo radical organizational changes to do so. As antigens from peripheral tissue are shuttled to SLOs, B cells there will interact with T cells and receive the signal to form “germinal centres” where they will proliferate, improve their affinity for the target, and diversify the types of antibodies they can produce to fight the invader. If that isn’t impressively dynamic enough, lymphoid tissue can also form de novo in adults in pathological settings such as infection, autoimmune disease, and graft rejection (‘tertiary lymphoid tissue’).
Because lymphoid tissue can form de novo, it seems like a reasonable target to try to engineer in the lab. In fact, a group from Cornell recently published a method to engineer tiny “immune organoids” by seeding relevant cell types onto a biomaterial scaffold and adding known important environmental cues (classic principles of tissue engineering). Their goal was to emulate the B cell environment and germinal centre reaction.
Specifically, the investigators fabricated gelatin hydrogels that were cross-linked by silicate nanoparticles. This provided attachment sites for cells, while also closely resembling the stiffness of the spleen when made at a specific concentration. B cells were added to the scaffold, but since B cells require a number of other signals from different SLO cell types, they also added stromal cells called fibroblasts that had been modified to express the important signaling molecules BAFF (B-cell activating factor) and CD40L. As a last cue to mimic the SLO environment, interleukin-4 was added to the culture media.
The investigators showed that B-cell proliferation and expression of markers relevant to the germinal centre were superior in their 3D culture system over 2D culture, the latter of which is often used in the laboratory setting. Furthermore, the addition of stromal cells at a sufficient density was important, supporting the hypothesis that they must be present to provide environmental cues to encourage the germinal centre response.
The most impressive readout, in my opinion, was their ability to show antibody class switching. To put this into context, antibodies perform numerous functions in the body to neutralize infection but, to do this, a variety of antibody types need to be made that all recognize the specific pathogen. Class switching is crucial, and thus by demonstrating class switching in their engineered organoids, the investigators have demonstrated that their system has biological relevance.
A good in vitro SLO model could be useful in a number of ways. It could help scientists understand how lymphoid tissue develops both naturally and in disease, and it could also be used to try to model the development of lymphomas (cancers of this tissue). On the therapeutic side, if these tissues could be used to train immune cells to respond to an antigen of the investigator’s choosing (e.g. one common to a specific virus or cancer), this could be relevant to the development of cell therapies.
Despite not being on the cultural radar, SLOs play a very important role in training immune responses, and I think it is fascinating that this can be partially mimicked in the laboratory setting.
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