For someone who doesn’t have a driving license, I spend far too much time thinking about CARs. Despite their most popular application, there’s no reason that CARs need only be used for anti-tumour offensives. Why, I recently covered a CAR-T_reg advance which holds tremendous potential for curbing chronic inflammation and maybe even driving germinal centre reactions. In the same vein, let’s talk about the newest model of CAR which goes after eosinophils, soaks up IL-4, and, thus, helps curb allergic airway inflammation.

The eosinophil, despite the demure Pointillism of its appearance, possesses a formidable armamentarium of inflammatory cytokines, cationic proteins, chemotactic agents, lipid mediators, and proteases. Thus, the contributions of the eosinophil to allergic asthma pathogenesis include things like gassing up and recruiting other granulocytes, activating CD4+ T cells (you should see the Class II expression on pulmonary eos: damn!), airway hyperresponsiveness, the damage-repair-damage patterns that eventually narrow one’s airways, and snot. So much snot.

We’ve indirectly attacked eosinophils in asthma via drugs to neutralize their many products, but everyone’s asthma is different. Like workout routines or potential boyfriend red flags, what is well-tolerated by one person may not work for another. After all, there are variants of asthma not driven by eosinophils. Further, in my opinion, the true key to long-term remission (dare I say, cure) for the allergic disease is bringing Th1 and Th2 responses in alignment, with neither predominating.

This work from Tsinghua University and Shanxi Medical University in China makes a valiant attempt to try to fill that need. Their CAR-Ts are first rendered immortal and more stem-like via the deletion of genes involved in metabolic regulation The resultant cells are a persistent, ever-renewing (but non-cancerous) population of CAR-Ts that the authors call CAR-T_IF to highlight their Immortal and Functional status This is logical. Given the omnipresent nature of allergy and a seemingly endless supply of granulocytes, we want an effector population that hangs around.

The TIFs herein target IL5Ra; ipso facto attacking eosinophils that highly express that receptor. The TIFs are also wired to continuously secrete an IL-4 mutein (mutant protein, get it?) which counteracts the pro-allergenic effects of the IgE-driving IL-4 and the generally chaotic IL-13. Incidentally, the IL-4 mutein was a promising immunotherapeutic for allergic asthma, but its short half-life rendered it DOA. Of course, the TIFs circumvent that problem since they secrete the mutein constantly.

Okay, but does it work?

Given the reduction in asthma symptoms and absence of pathophysiological changes in OVA-sensitized mice experiencing eosinophilic inflammation, I’d say it does. I worry, though. Whenever we find ourselves depleting an entire population of cells indiscriminately, I worry. Eosinophils are not a monolith. You should ask my dear friend and eosinophil maven, Dr. Amali Samarasinghe. Her research programme is an ode to the functional versatility of this excitable granulocyte. Amali’s group has identified a Siglec-hi eosinophil subset that supports anti-viral (i.e. Th1) responses in the lung. To me, such an observation represents that moment of immune alignment I was talking about, where everyone closes ranks to protect a vital organ.

Therefore, it’s hard to say if the TIF-infused humans would be more prone to pulmonary viral infections or even tumours because helpful eosinophil subsets are now simply gone. In my opinion, when we eradicate an entire population of cells, we certainly rid ourselves of all their pathological effects, but the price is all the good that those very cells can (and do) bring.

Don’t get me wrong: what Jin et al have accomplished here is provocative and exciting. This work continues to inspire our imaginations on how to deploy CAR-Ts, and, that in itself is nothing to cough at. I’d venture so far as to say that it is…breathtaking!

Source:
Jin, G., Liu, Y., Wang, L. et al. A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice. Nat Immunol 25, 1059–1072 (2024). https://doi.org/10.1038/s41590-024-01834-9

InterferonGuy

I’m a T cell jock who often wonders why Jeopardy never had a “Cytokines” category. The liver is my favourite organ: a metabolic workhorse AND an immunological hub?! The range and work ethic are inspiring.

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