Protein Handshake Holds Key to Immune Response

A firm handshake between proteins on immune cells is important for the body’s ability to fight infection. Meanwhile, a weak grip helps explain the poor immune deficiencies caused by a rare genetic disorder.

A new study led by Georgia Tech and Emory University researcher Cheng Zhu explores the role of physical force on the immune system’s ability to fight an infection. The team’s discoveries could lead to new therapies that boost immune responses and improve the outcomes of patients battling a rare and devastating disease.

“With this research, we’ve shown how dynamic and physical the immune system truly is,” said Zhu, Regents' Professor and J. Erskine Love Jr. Chair in the Wallace H. Coulter Department of Biomedical Engineering (BME).

The work focuses on the interaction of B cells and T cells in the body’s immune system via two proteins — CD40 on B cells and CD40L on T cells — in an immune deficiency disease called X-linked Hyper IgM syndrome, or X-HIgM. It’s a genetic disorder affecting two out of every million newborn boys, 80% of whom die before the age of 25.

The researchers found mechanical forces generated by these interactions create a “catch bond” between the proteins. It’s like a strong handshake that only gets firmer when each person tries to pull away.

When the bond is strong, it causes T cells to signal B cells they need to make antibodies to fight an invading pathogen. In fact, the B cells can actually switch gears, producing antibodies that are different from what they had been making.

But people with X-HIgM have damaged CD40L proteins, resulting in weak bonds, poor signaling, and the inability to make the right antibodies.

The team published their findings in Science Advances. The work emphasizes the role of mechanotransduction — the conversion of physical force into chemical activity — in the immune system.

“What surprised us was the discovery of the catch bond between CD40 and CD40L and how it relates to mechanotransduction,” said Zhu. “Mechanical force doesn’t just passively exist during T cell and B cell interactions — it actively enhances signaling and ensures robust antibody responses.”

Zhu’s fellow principal investigators in the study included Georgia Tech researcher Ankur Singh and Juergen Wienands of the University Medical Center Göttingen in Germany. Lead authors were former BME PhD student Stefano Travaglino and former postdoc Hyun-Kyu Choi (now an assistant professor at Yonsei University in South Korea).

Training Camp for B Cells

In the body’s defense system, B cells are produced in the bone marrow and migrate to a part of the lymph nodes called the germinal center. 

“It’s like a training camp where B cells undergo improvement processes, including affinity maturation and antibody class switch, enhancing their ability to make effective antibodies,” Travaglino said. 

B cells interact with and receive instructive signals from T cells to make antibodies that are most effective in coping with the pathogen invader. It’s a process that relies heavily on the interaction of CD40 and CD40L.

Using techniques like fluorescence microscopy, the researchers were able to look closely at activity in germinal centers. They used force spectroscopy tools like the biomembrane force probe which revealed that the strong, tugging handshake is suppressed by X-HIgM mutation. 

The findings suggest that the physical environment and activity within the germinal center is just as important as the chemical signals at play between the proteins. By demonstrating how X-HIgM mutations impair catch bonds, the researchers provided a mechanistic explanation for the condition’s antibody deficiencies — knowledge that could open the door to future innovations in therapeutic intervention and immunotherapy.

Singh called the team’s findings “nothing short of revolutionary.”

“The significance of the research extends far beyond understanding X-HIgM, offering a fresh perspective on how to approach a variety of immune disorders,” he said. “As this field of study evolves, the potential for advancements in immune therapies looks bright.”

CITATION: Hyun-Kyu Choi, Stefano Travaglino, Matthias Münchhalfen, Richard Görg, Zhe Zhong, Jintian Lyu, David M. Reyes-Aguilar, Jürgen Wienands, Ankur Singh, and Cheng Zhu. “Mechanotransduction governs CD40 function and underlies X-linked Hyper IgM syndrome,” Science Advances. DOI: 10.1126/sciadv.adl5815

FUNDING: This research was supported by National Institutes of Health grants U01CA250040, U01CA280984, R01CA238745, and R01CA266052; The Hyper IgM Foundation AWD-004331; German Research Foundation SFB TRR 274, project A08; National Research Foundation of Korea (NRF) grant RS-2024-00337196; and the Yonsei University Research Fund 2024-22-0036. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of any funding agency.