A recent paper published in Cell Reports by the Oxenius group at the Institute of Molecular Biology (IMB) has uncovered an intriguing aspect of immune cell behavior, specifically focused on the process of centrosome inheritance in CD8+ T cell division and its implications for memory cell generation. This study sheds new light on how CD8+ T cells, vital players in adaptive immune responses, produce diverse progeny with distinct functional fates after activation, contributing to our understanding of immune cell differentiation.
CD8+ T cells are a pivotal component of the adaptive immune system, tasked with recognizing and eliminating infected or malignant cells. They are particularly critical for combatting intracellular pathogens, such as viruses, as well as for mounting anti-tumor responses. When naïve CD8+ T cells encounter their specific antigen, they undergo activation and start proliferating. This leads to the differentiation of these cells into two main types: short-lived effector cells that immediately perform immune functions and long-lived memory precursor cells that ensure immune protection upon re-exposure to the pathogen.
While the process by which a single, naïve T cell divides to give rise to these diverse progeny is well-known in many respects, the precise mechanisms that control this fate diversification remain unclear. One hypothesis that has gained traction in recent years is that asymmetric cell division (ACD) plays a crucial role in determining the fate of the daughter cells. ACD is characterized by the unequal distribution of cellular components, including organelles, proteins, and other cargo, which leads to the generation of daughter cells with distinct developmental fates. This unequal inheritance results in one daughter cell becoming more effector-like, ready to execute immune responses, while the other becomes more memory-like, poised for long-term protection.
The team behind the new study hypothesized that centrosomes, the key microtubule-organizing centers within cells, might be differentially inherited by daughter cells during the first division of naïve CD8+ T cells. Centrosomes are essential for organizing the microtubules that form the mitotic spindle, ensuring that cell division proceeds accurately. Given their crucial role in cell division and organization, the researchers speculated that specific partitioning of centrosomes during T cell activation could influence the differentiation of daughter cells into either effector or memory precursor cells.
To investigate this, the team developed two distinct centrosome labeling techniques that allowed them to track the inheritance of mother and daughter centrosomes during the first division of activated CD8+ T cells. Their experimental design aimed to observe whether centrosomes were partitioned asymmetrically during the initial cell division and how this might impact the fate of the resulting progeny.
The results of the study were striking. The researchers discovered that in over 90% of the first divisions of activated CD8+ T cells, the mother centrosome was preferentially inherited by the daughter cell that exhibited more effector-like characteristics. This pattern of centrosome inheritance was strikingly consistent, suggesting that centrosomes may serve as more than just structural components of cell division; they could play a critical role in guiding the fate decisions of daughter cells.
In further experiments, the team tested the effects of randomizing centrosome inheritance by artificially disturbing the preferential inheritance of the mother centrosome. This manipulation resulted in a significant shift in the fate of the daughter cells. Specifically, there was a higher frequency of effector-like progeny at the expense of memory-like cells, highlighting the importance of directed centrosome inheritance in controlling the balance between effector and memory cell formation.
These findings are of great significance as they suggest that centrosomes are not simply passive participants in cell division but may actively contribute to the diversification of immune cell fates. By directing the inheritance of centrosomes, a naïve CD8+ T cell can influence whether a daughter cell takes on an effector role or becomes a memory precursor. This discovery offers a new layer of complexity in our understanding of immune cell differentiation and could have implications for how we approach immunotherapy and vaccine development, where promoting the generation of long-lived memory cells is often a key goal.
The concept of centrosome inheritance influencing immune cell fate adds a new dimension to the broader understanding of asymmetric cell division in immune responses. It challenges the traditional view of cell division as a simple process of replicating cellular components and emphasizes the importance of cellular organization and structure in shaping the functional outcomes of immune cells. This insight also opens up new avenues for future research, as scientists may explore whether centrosome inheritance plays a role in other immune cells or even in the development of other complex tissues.
This work is part of a broader effort to decode the molecular and cellular mechanisms that govern immune cell behavior. In the case of CD8+ T cells, understanding how the cells differentiate into effector and memory populations is crucial not only for understanding basic immunology but also for improving clinical strategies aimed at enhancing immune responses. The ability to selectively manipulate memory precursor generation could lead to more effective vaccines or therapeutic interventions, particularly in the context of viral infections or cancer, where long-term immunity is critical.
Moreover, this research highlights the potential for targeted interventions in immune cell fate determination. If centrosome inheritance can be harnessed to favor the generation of memory cells, it could provide a powerful tool in immunotherapy, where the long-term persistence of immune cells is often essential for effective defense against chronic diseases. Conversely, enhancing effector cell generation might prove beneficial in situations where a rapid immune response is needed, such as in the early stages of an infection.
Reference: Niculò Barandun et al, Targeted localization of the mother centrosome in CD8+ T cells undergoing asymmetric cell division promotes memory formation, Cell Reports (2025). DOI: 10.1016/j.celrep.2024.115127