Fraternity forged in Il-2
Happy T cell Activation Day! 3/28, get it? I swear, I don’t know who came up with this, but it delights me so!
I talked about fratricide the last time, but T Cell Activation Day is about the fellowship that exists between CD4+ and CD8+ T cells, a bond built in IL-2.
IL-2 is cytokine royalty, and its biology really came into focus in the late 1970s and early 1980s. One of my favorite bits of IL-2 lore is an experiment from Robert Gallo’s lab where bone marrow cells were cultured with conditioned medium siphoned off PHA-activated PBMC. What they found was a dramatic outgrowth of exclusively T cells. Can you imagine being that grad student or postdoc who clocked this observation? I’d lose sleep thinking about what that esoteric “thing” was in that conditioned medium that seemingly promulgated only T cells. This observation was no flash in the pan either: Kendall Smith’s group at Dartmouth maintained murine T cells in culture for 4 months using the conditioned medium method. Personally, I don’t recommend maintaining primary T cells in culture for longer than two weeks, but…different times.
IL-2’s lore grew with time. In 1997, Alfred Chang’s group at UMich was exploring the mechanisms involved in tumour rejection by T cells found in tumour-draining lymph nodes. Immunomagnetic separation of tumour-draining CD4s and CD8s revealed that it was the CD4s that made a sh*t-ton of IL-2, and the CD8s…well, attempts were made, but making gamma interferon was the real priority for them. Pure cultures of CD4s secreted cytokine when challenged with tumour antigen but were not cytolytic. Relatedly, the CD8s alone were cytotoxic, but this degree of cytotoxicity paled in comparison to mixed CD4+CD8 cultures. Intriguingly, adding IL-2 exogenously to pure CD8 cultures did not enhance their anti-tumour activity. Taken together, these experiments establish a few things:
i. There is a clear division of labour here: CD4s bring the IL-2 while CD8s, primed by it and other CD4-secreted cytokines, proliferate and do murder. Ergo:
ii. CD4s and CD8s need each other. They’re stronger together when trying to drive out a cancerous scourge.
iii. The role of CD4s extends beyond IL-2 production: we now know that they also provide stimulatory and survival signals to their brethren via homotypic interactions. CD4-sourced interferon and GM-CSF also makes for mature, more efficient antigen-presenting cells. That’s why exogenously adding IL-2 to cultures of CD8s only worked…fine. Nothing compared what was seen in mixed cultures, because:
iv. Teamwork makes the dream work.
The fraternity forged in IL-2 has been richly applied to current immunotherapeutic approaches. Intravenous IL-2 supplementation is an enduring approach for kidney and skin cancers. The idea is to bind the IL-2 receptors of CD4+ T cells to create a positive feedback loop that floods the system with IL-2, thereby priming anti-tumour programmes. On paper, this is sound and lovely, but Aldesleukin comes with debilitating toxicity. But what if we could target IL-2 rather than infusing it systemically? There are companies and research groups doing just that via clever inducible IL-2 systems which would only become active within a tumour.
Since this is my blog, I am allowed a bit of bias. Thus, I feel no shame in saying that what I am excited about is CD4-CAR and CD4-TCR-T immunotherapies. Of course, it is logical to focus on CD8s when designing immunotherapies, after all, they’re the killers. But based on everything I’ve written, do you see why adoptive CD4 T cell therapy makes sense? You have before you a bunch of antigen-specific cells which, upon encountering a tumour, will secrete cytokines that shape the intertumoural milieu. Plus, there is so much potential for multiplexing: consider CD4 and CD8s with different tumour antigen and HLA-restrictions infused into a patient! I also envision a world where these immunotherapeutic approaches could benefit the treatment of infectious diseases. Like, let’s face it: antibiotics are over; hanging by a thread…but, I digress!
Ultimately, so much of adoptive cell immunotherapy is relationship management. We want to avoid civil strife vis-à-vis fratricide, and we want to promote fraternity but not to the extent of cytokine release syndrome or a situation where the helpers themselves become leukemias. As cryptic as the bureaucracies of biology are, understanding those covenants is what leads to better health.
Happy T cell Activation Day once again: may the IL-2 rise when it should, and the IL-7 prevail and keep things good.
Until the next time: peace!
