Uncovering the signals that govern the fate of T helper cells is a big step toward improved vaccine design
Follicular helper Tcells (TFH cells), a rare type of immune cell that is essential for inducing a strong and lasting antibody response to viruses and other microbes, have garnered intense interest in recent years but the molecular signals that drive their differentiation had remained unclear. Now, a team of researchers at the La Jolla Institute for Allergy and Immunology has identified a pair of master regulators that control the fate of TFH cells.
Follicular helper T cells (cells with green surface markers) interact closely with B cells (cells with orange surface markers) to facilitate the proliferation of B cells and the production of high affinity antibodies. The interaction site is shown in yellow, DNA in blue.
Credit: Joyce Hu, La Jolla Institute of Allergy and Immunology
Their finding, published in this week's online edition of Nature Immunology, holds great promise for improved vaccine design and may lead to new treatments for immune disorders and possibly even cancer. "Almost all licensed human vaccines work on the basis of inducing a long-term, protective antibody response," says the study's lead author Shane Crotty, Ph.D., a professor in the Institute's Division of Vaccine Discovery. "Being able to enhance or increase the frequency of follicular helper T cells may be an excellent approach for better vaccine design."
Before B cells can launch a full-blown antibody response against invading pathogens they undergo a tightly orchestrated, multi-step maturation process aided by TFH cells. Often compared to a miniaturized Darwinian struggle for survival, this process selectively promotes the proliferation of B cells that produce high-affinity antibodies and weeds out those that produce less potent ones.
"B cells compete for TFH cells to survive," explains postdoctoral researcher and first author Youn Soo Choi, Ph.D., "Only those B cells that produce highly specific antibodies attract TFH cells and are able to proliferate." The survivors undergo successive rounds of mutation and selection resulting in better and better antibodies during the course of an immune response.
"TFH cells are essential for the production of most types of antibodies and defects in TFH function or frequency can have dramatic effects," says Crotty. "It may be particularly important when antibody targets are difficult to recognize and B cells need to explore a bigger mutational landscape. A better understanding of how these cells are produced could really make a difference in how likely it is that your body manages to make good antibodies against an infection."
In an earlier study, Crotty's team had identified the BCL6 gene as a crucial mastermind in the differentiation of TFH cells but important pieces of the puzzles had still been missing. A combination of functional genomics and bioinformatics analysis allowed Choi to narrow the list of potential candidates down to a pair of transcription factors, LEF-1 and TCF-1. Transcription factors act as master switching by binding to regulatory regions in the genome, where they modulate gene activity. He then confirmed the importance of LEF-1 and TCF-1 for the differentiation of TFH cells with the help of mice genetically engineered to lack the genes encoding either LEF-1 or TCF-1.
"Their activity pre-programs CD4+ T cells to respond to TFH induction signals," says Choi. "It seems very likely that any perturbation that results in lower levels of these transcription factors could decrease the likelihood that T cells differentiate into TFH cells."
As a matter of fact, individual differences in the predilection to make more TFH cells could explain why some individuals produce highly efficient antibodies against HIV, while most individuals are unable to mount a potent immune response. "It is very difficult to create high-affinity antibodies for HIV, which are necessary to neutralize virus," explains Crotty. "Interestingly, it turns out that those individuals that are able to make broadly neutralizing antibodies against HIV, have unusually elevated levels of highly functional memory TFH cells. We speculate that these people may have a genetic bias to produce a really good TFH response but we haven't identified it yet."
The research was supported by the La Jolla Institute for Allergy and Immunology, the American Cancer Society (RSG-11-161-01-MPC), and the National Institutes of Health (AI105351, AI112579, AI115149, AI119160, AI113806, AI109976, AI063107 and AI072543).
Full citation: "LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6." Youn Soo Choi, Jodi A Gullicksrud, Shaojun Xing, Zhouhao Zeng, Qiang Shan, Fengyin Li, Paul E Love, Weiqun Peng, Hai-Hui Xue & Shane Crotty. doi:10.1038/ni.3226
ABOUT LA JOLLA INSTITUTE
La Jolla Institute for Allergy and Immunology is dedicated to understanding the intricacies and power of the immune system so that we may apply that knowledge to promote human health and prevent a wide range of diseases. Since its founding in 1988 as an independent, nonprofit research organization, the Institute has made numerous advances leading towards its goal: life without disease®.
Gina Kirchweger | EurekAlert!
Complete skin regeneration system of fish unraveled
24.04.2018 | Tokyo Institute of Technology
Scientists generate an atlas of the human genome using stem cells
24.04.2018 | The Hebrew University of Jerusalem
At the Hannover Messe 2018, the Bundesanstalt für Materialforschung und-prüfung (BAM) will show how, in the future, astronauts could produce their own tools or spare parts in zero gravity using 3D printing. This will reduce, weight and transport costs for space missions. Visitors can experience the innovative additive manufacturing process live at the fair.
Powder-based additive manufacturing in zero gravity is the name of the project in which a component is produced by applying metallic powder layers and then...
Physicists at the Laboratory for Attosecond Physics, which is jointly run by Ludwig-Maximilians-Universität and the Max Planck Institute of Quantum Optics, have developed a high-power laser system that generates ultrashort pulses of light covering a large share of the mid-infrared spectrum. The researchers envisage a wide range of applications for the technology – in the early diagnosis of cancer, for instance.
Molecules are the building blocks of life. Like all other organisms, we are made of them. They control our biorhythm, and they can also reflect our state of...
University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.
Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.
Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.
Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...
Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.
The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...
13.04.2018 | Event News
12.04.2018 | Event News
09.04.2018 | Event News
24.04.2018 | Information Technology
24.04.2018 | Earth Sciences
24.04.2018 | Life Sciences