New Insights on Cell Structure’s Role in Immune Function

Research has unveiled critical links between cell structure and immune system functionality, particularly regarding a protein known as ARPC5. Mutations in this protein, which is part of the Arp2/3 complex, have been shown to severely compromise immune responses, leading to conditions such as immunodeficiency and a heightened risk of fatal sepsis in early life. This finding stems from a study led by Michael Way at the Francis Crick Institute, reported in the journal Science.

The cytoskeleton, an internal framework of cells primarily composed of the protein actin, is vital for maintaining cell shape and driving movement. Disruption in the proteins that manage the actin cytoskeleton can result in dire health consequences. Way states, “This is a rare and devastating condition, and until recently, it wasn’t clear how these mutations lead to such severe illness.” The only known effective treatment currently involves early bone marrow transplantation to replace defective immune cells.

Linking Mutations to Immune Dysfunction

To investigate how ARPC5 mutations compromise immune function, Way and his team examined the immune systems of mice with and without these mutations. Their findings revealed a significant disparity between healthy and ARPC5-deficient mice. According to Shaina Chor Mei Huang, “The inflammation in adult mice with ARPC5 deficiency mirrored what we see in people with the same mutation.” At eight weeks old, these mice showed signs of being underweight, with inflamed and damaged intestines, leading to sepsis due to bacterial infiltration that their immune systems could not manage.

Interestingly, the mice were healthy at four weeks of age, which coincided with the weaning stage. This period marks a transition in their gut microbiome, the community of microorganisms residing in the intestines. Luiz Ricardo C. Vasconcellos notes, “We next looked at whether the interaction between the immune system and the microbiome leads to intestinal inflammation.” The team confirmed that bacterial composition shifted significantly at four weeks, indicating the microbiome’s role as a potential trigger for inflammation.

Restoring Immune Function

To better understand the microbiome’s impact on immune cell interactions, the researchers delved into the dynamics between various immune cells. They discovered that communication between macrophages and T regulatory cells in ARPC5-deficient mice had deteriorated, disrupting the immune system’s balance. Vasconcellos explains, “We also saw that macrophages had lost their usual shape, becoming elongated, and could no longer eat or kill bacteria effectively.”

Significantly, the team found that conducting a bone marrow transplant to replace the dysfunctional immune cells in the mice effectively reversed the inflammation. This suggests a similar treatment could benefit individuals suffering from ARPC5 mutations.

Way concludes, “We now know that immune cells with key structural deficiencies are unable to respond in the right way to gut microbes, leading to the problems seen in patients.” The implications of this research extend beyond ARPC5 mutations. The structural deficiencies in macrophages are also present in various other conditions, including inflammatory bowel disease. Ongoing research aims to explore the role of these deficient macrophages in other body systems, such as the lungs.

This groundbreaking work highlights the importance of the cytoskeleton in maintaining a well-functioning immune system and opens new avenues for potential treatments in related health conditions. More information can be found in the study by Vasconcellos and colleagues, titled “Branched actin networks mediate macrophage-dependent host-microbiota homeostasis,” published in March 2025.