A Search for Cell Identity

When immunologist Roxane Tussiwand, Ph.D., was eleven, all she wanted was answers. Answers to the puzzling questions surrounding her three-year-old brother’s leukemia, a type of blood cancer.

"The incapacity to grasp what was going on was the trigger for me,” Tussiwand recalls. “I needed to understand more." This urge to make sense of what had happened to her brother, who eventually recovered, drove Tussiwand to study childhood leukemia as an undergraduate student in Italy.

During her doctoral training in Switzerland, Tussiwand became interested in how stem cells in the bone marrow mature into invader-fighting immune cells (white blood cells), a process that is disrupted in leukemia. When the body senses foreign material, different combinations of molecular and genetic signals guide the stem cells to develop into the specific immune cells needed for any given defensive response.

"But what exactly happens in between the stem cells and their fate is like a black box," says Tussiwand, who recently joined NIDCR as an Earl Stadtman Investigator. NIH’s Stadtman program recruits exceptional, early-stage scientists to carry out innovative, high-impact research.

By shedding light on the factors that mold immune cell identity and our immune responses, Tussiwand’s efforts could help scientists better understand autoimmune syndromes, infection, and cancer—the disease that had so puzzled her as a child.

At NIDCR, Tussiwand focuses on a group of immune cells—dendritic cells—that often reside in the tissues lining the oral cavity. Dendritic cells survey their surroundings for potentially harmful material and grab onto, engulf, and digest foreign particles, bacteria, or virus-infected cells. They then display bits of the germs (antigens) on their outer membranes, which helps train other immune cells, such as T cells, to recognize the pathogens and defend the body. Tussiwand’s goal is to examine the molecular cues and timing that send stem cells down their destined path to become dendritic cells, a process called differentiation.

Previous research has shown that the development of a subset of dendritic cells that train T cells to respond to pathogen-infected cells requires an activator protein called BATF-3. However, as a postdoctoral researcher at Washington University in St. Louis, Tussiwand challenged that notion. Her team found that in the absence of BATF-3, a separate but related set of signals can trigger development of these dendritic cells. This pathway is active during infections, and according to the scientists, could be harnessed to boost immune responses to vaccines.

While some dendritic cells specialize in displaying antigens on their surfaces, another type, called plasmacytoid dendritic cells, produces proteins that keep viruses from spreading. Scientists knew little about these cells. But Tussiwand, as an assistant professor at the University of Basel in Switzerland, worked with her group to map out the cells’ origins and the molecular cues that seal their fates. Along the way, her team also identified a new group of cells that look and act like the protein-producing plasmacytoid dendritic cells but can also display antigens on their outer membrane. This feature, according to the researchers, may explain previous findings that some dendritic cells can trigger immune responses against tumors in patients with melanoma, a deadly type of skin cancer.

At NIDCR, Tussiwand is working to investigate what her earlier findings in mice can tell us about immunity in humans. Dendritic cells may also play a pivotal role in autoimmunity, and her research could shed light on autoimmune diseases like Sjögren's syndrome, which causes dry eyes and mouth. She plans to extend her research to other immune cells, tracing the factors that shape their development and function within the immune system.

As a principal investigator running her own lab, Tussiwand says, "You have to be your own ‘avvocato del diavolo,'" which means ‘devil's advocate’ in her mother tongue, Italian. She stresses the importance of self-discipline and self-reflection in asking fundamental questions that will yield the best science. "At the NIH, you will be the limiting factor of your research, as all opportunities are open for reach.”

References

Compensatory dendritic cell development mediated by BATF-IRF interactions. Tussiwand R, Lee WL, Murphy TL, Mashayekhi M, KC W, Albring JC, Satpathy AT, Rotondo JA, Edelson BT, Kretzer NM, Wu X, Weiss LA, Glasmacher E, Li P, Liao W, Behnke M, Lam SS, Aurthur CT, Leonard WJ, Singh H, Stallings CL, Sibley LD, Schreiber RD, Murphy KM. Nature. 2012 Oct 25;490(7421):502-7. doi: 10.1038/nature11531. Epub 2012 Sep 19. PMID: 22992524; PMCID: PMC3482832.

Distinct progenitor lineages contribute to the heterogeneity of plasmacytoid dendritic cells. Rodrigues PF, Alberti-Servera L, Eremin A, Grajales-Reyes GE, Ivanek R, Tussiwand R. Nat Immunol. 2018 Jul;19(7):711-722. doi: 10.1038/s41590-018-0136-9. Epub 2018 Jun 20. PMID: 29925996.

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