Will Bailis

Description of Research Expertise

The Bailis Lab studies how diet and the environment shape immune cell identity, to develop novel approaches for targeting immune responses during infection and cancer. Every cell on Earth, whether bacterium or T cell, runs on the same basic biology: it takes in nutrients, breaks them down, and uses them to build the proteins that let it function. The immune system draws on this same biology. When a threat appears, immune cells must rapidly shift from a resting state into an entirely new identity and function to try clearing it. Central to that identity shift, cells rewire transcription factors and gene networks to provide themselves with a new set of instructions, a strategic plan. We study the cellular logistics required to enable that plan: how metabolism and protein synthesis (processes conserved across all of life) are uniquely deployed to build the cell-type specific identities and capabilities of the immune system. We have found that the limits of that shared machinery dictate cell identity as much as the transcriptional instructions and are now working to answer:

1) What gives an immune cell the capacity to carry out the instructions it receives? When a T or B cell recognizes a threat, it receives instructions from its antigen receptor, cytokines, and other factors to transform: to grow, divide many times over, and take on an entirely new identity. Receiving those instructions is not the same as being able to carry them out. A cell must physically rebuild itself into something new, and that rebuilding has metabolic requirements of its own. We've found that a lymphocyte’s capacity to execute this transition is set by how much NAD it produces. NAD is one of the most fundamental metabolites in biology and functions as the electrical wiring of a cell. Despite its universal importance and role in hundreds of reactions, we have shown NAD plays a highly specific role in T and B cell biology at the time they respond to antigen. Our work suggests that cellular NAD levels determines whether and how completely a program can run (e.g. effector versus memory), not by rewriting the instructions, but by setting whether the cell can build what it needs to meet a program’s demands. This capacity varies even among cells receiving an identical signal: single-cell differences in NAD, established within hours of activation and before a cell ever divides, predict how fast it proliferates, which functions it acquires, and whether it persists into long-term immune memory. We are working out this machinery, including how it lets a cell "read" the strength of a signal. We're applying these findings to build more durable cell therapies for cancer, and to understand how diet shapes vaccine responses and autoimmunity.

2) How does the cellular economics of biosynthetic supply vs demand underlie immune cell identity? Immune cells routinely move across dynamic environments, from the nutrient-rich bloodstream into nutrient- and oxygen-scarce tissues like a tumor, a site of infection, an inflamed organ. There, the demands placed on a cell can suddenly outstrip its capacity to meet them, and how a cell manages that gap determines whether it stays functional or slides toward dysfunction and exhaustion. We've found that immune cells can expand their capacity to meet rising demand by reprogramming their biosynthetic machinery through stress-adaptation pathways like the integrated stress response, and that modulating this capacity changes how durable T cells are in hostile environments like tumors. We believe this reframes T cell fates like exhaustion not as a fixed genetic fate, but as what happens when demand outpaces capacity, pointing to new ways to make immunotherapies more resilient. We are now interested in investigating how T cell stress resilience as well as different facets of this biosynthetic machinery, like distinct modes of mRNA translation and amino acid handling, underpins T cell identity and can be therapeutically manipulated.

3) How does the nutrient environment set the capacity of the immune system? This logic scales from the single cell to the whole body. Nearly a billion people live with restricted access to food, and infection in the setting of malnutrition remains a leading cause of death worldwide, particularly in children. However, we understand little about why. In models of chronic malnutrition, we've found that immune vulnerability to infection persists for months after animals fully recover their weight and immune cell numbers, as if the immune system retains a memory of scarcity. We are now seeking to define the mechanisms behind this durable reprogramming, aiming to identify dietary components that could help rebuild immune capacity in vulnerable populations, and investigating how immune cells detect dietary change and help coordinate the body's response to it.