Effective vaccines may depend on the ability of a key cellular mechanism to limit the immune system’s “brakes” on developing neutralizing antibodies, according to a new paper published by a team of scientists from the Hackensack Meridian Center for Discovery and Innovation (CDI).
The specialized immune cells could bring a key new advantage to fostering long-term immunity to a host of diseases, including the viral infection that causes COVID-19, according to the new paper in the Proceedings of the National Academy of Sciences.
“Currently, we do not have good vaccines against all life-threatening pathogens,” said Hai-Hui “Howard” Xue, M.D., Ph.D., a CDI faculty member. “Some of the failure to develop productive vaccines can be attributed to insufficient immune responses being elicited. Blocking the brakes, in a temporally controlled manner, has the strong potential to enhance immune responses and improve vaccine efficacy.”
T follicular helper (Tfh) cells are a specialized subset of CD4+ T cells which help B cells produce protective antibodies – and this happens within follicles of the lymph system (spleen, lymph nodes, and tonsils).
The Tfh cells express high levels of two transcription factors called Tcf1 and Lef1. The new study found that these proteins help control the “brakes” on the immune system – the brakes being the immune checkpoints CTLA4 and LAG3. CTLA4 and LAG3 are essential to stop runaway immune response (or autoimmune conditions).
But they can slow/inhibit something like a wanted vaccine response.
Removing the Tcf1 and Lef1 protein made the brakes (the checkpoints) act so strongly that the immune response, especially antibody production, was halted.
Overall, the Tcf1 and Lef1 transcription factors restrain accessibility of the “brake” genes. This shows that vaccines could be dependent on harnessing this “suppression of the brakes” pathway to bolster an immune response.
“Dr. Xue’s detailed investigations into the immune system have immediate implications for cancer and infectious disease therapy and prevention,” said David S. Perlin, Ph.D., senior vice president and chief research officer of the CDI.
Blocking the brakes is at the center of much continuing research. In fact, the 2018 Nobel Prize in Physiology or Medicine was given to the discoverers of the “brake” mechanism – which opened up many current avenues of research.
“Based on current success of checkpoint blockade immunotherapy in cancers, the same concept can be applied to improve vaccine efficacy” added Xue.