Researchers find human factor that causes the maturation of T helper -
A powerful arm of the immune system is the production of antibodies that circulate in the blood and neutralize pathogens invaders. Although B cells actually produce antibody protein, the process is aided by neighboring T cells, including B cells with shower cytokines to make them churn out antibodies of high quality protein - and remember how make. Given the essential role of T cells "helper", researchers have long sought to define the biological signals that promote their development. So far, the best candidates were only minor effects on human immune cells.
Now, an article published by La Jolla Institute (LJI) researchers in the July 2016 issue Nature Immunology identifies a human factor that causes the maturation of T helper cells called helper T cells follicular (TFH) cells. This factor, a cytokine known as activin A, specifically entails maturation of human Tfhs and different factors which act similarly in mice. This work, conducted LJI biologist vaccine Shane Crotty, Ph.D., fills a gap in knowledge by revealing signals that could be therapeutically targeted either stimulate immune responses to fight against the infection or to slow down, in the case of a autoimmune disease.
"most human vaccines work by inducing an antibody response. For these responses are of high quality you need for TFH cells," says Crotty, professor in the division of LJI discovery of a vaccine. "Our study has identified an unexpected signaling protein that is very good to induce the maturation of human TFH cells. Knowing this could help us learn how to design more potent vaccines."
One reason for achieving the objective has been difficult is that previously, many research laboratories, including Crotty, had conducted experiments on mouse models and found that the key factors Tfh of differentiation in rodents differed from those governing human immune cells. Thus, focusing on human factors alone, Crotty laboratory set up an impartial search 2,000 candidate proteins, automated strategy called "high-throughput screening."
Specifically, their task was to comb through a collection or "library" of candidates signaling molecules and testing them one by one to see if anyone could stimulate maturation of immature human TFH cells cultured. the best candidate out of the screen is a secreted protein called activin a member of the family of cytokines.
followed by experiments confirmed that exposure to activin a stimulated immature TFH cells to express genes encoding receptors and other factors typical in mature cells, while the fluorescence microscopy revealed activin a protein in tonsil lymphoid tissues near sites Tfh differentiation has taken place and in close proximity with the cell B. This circumstantial evidence has demonstrated that activin a has was produced in the "right place".
Other comparisons explored and confirmed the rodent / human divergence that had proven to be such an obstacle. The incubation of immature mouse T cells with activin A did not actually encourage their maturation, while the treatment of immature Tfhs macaque monkeys with activin A did.
The discovery of a single primate mechanism is intriguing from an evolutionary point of view, as the biochemical pathways regulating immune activities are often highly conserved in mammals. "Mice are extremely useful in biomedical research in helping us to understand how genes and proteins function," says Crotty. "But from time to time, we see the differences between species, and cell differentiation Tfh was one of those case. "
Finally, the team showed that for activin a boost Tfh maturation, it must activate the DNA-binding molecules called downstream SMAD2 / 3. They discovered this by treating immature TFH cells with the drug Galunisertib, which mutes the SMAD2 signaling, and found that the cells became refractory to activin signals. this experiment not only defined a biochemical pathway, but means that a medicament exists for potentially block T cell "help" keeping the TFH cells in an immature state. - the most obvious application is an autoimmune disease
"Many autoimmune diseases exhibit excessive production of TFH cells, which can lead to the formation of autoreactive antibodies, "explains Michela Locci, Ph.D., lead author of the study and a postdoctoral fellow in the laboratory Crotty. "In at least two of them - the rheumatoid arthritis and systemic lupus erythematosus -. The level of activin A in the blood is higher than normal, suggesting that it contributes to the differentiation Tfh deregulated in these diseases "Locci found these promising associations, but warns that it is too early to say whether Galunisertib, being tested as an anti-cancer drug in clinical trials, could normalize Tfh excess activity in the autoimmune disease.
Overall, the predominant interest Crotty laboratory is in the antibody-based immunity regarding vaccine development. One way that vaccines work is establishing cells B long-term memory when exposed to a recall of deadly pathogen they saw the invader before (albeit in a form of harmless vaccine) and are willing to do antibodies. When TFH cells were discovered in 01, scientists quickly realized that they were necessary for both the development of these memory B cells and instruct them on how to make high affinity antibodies.
"Generating more TFH cells could promote cell more powerful B responses and increase the production of long-term memory cells," says Crotty. "From the standpoint of the design of the vaccine, it may be desirable encourage the development of Tfh cells in vivo since the production of a protective vaccine requires the production of antibodies. "Knowing that activin a is the main source of" encouragement "could lead his laboratory to a new research, this both small molecules potentially useful for transforming activin A on the time of vaccination, instilling more lasting memories in B cells
Now, an article published by La Jolla Institute (LJI) researchers in the July 2016 issue Nature Immunology identifies a human factor that causes the maturation of T helper cells called helper T cells follicular (TFH) cells. This factor, a cytokine known as activin A, specifically entails maturation of human Tfhs and different factors which act similarly in mice. This work, conducted LJI biologist vaccine Shane Crotty, Ph.D., fills a gap in knowledge by revealing signals that could be therapeutically targeted either stimulate immune responses to fight against the infection or to slow down, in the case of a autoimmune disease.
"most human vaccines work by inducing an antibody response. For these responses are of high quality you need for TFH cells," says Crotty, professor in the division of LJI discovery of a vaccine. "Our study has identified an unexpected signaling protein that is very good to induce the maturation of human TFH cells. Knowing this could help us learn how to design more potent vaccines."
One reason for achieving the objective has been difficult is that previously, many research laboratories, including Crotty, had conducted experiments on mouse models and found that the key factors Tfh of differentiation in rodents differed from those governing human immune cells. Thus, focusing on human factors alone, Crotty laboratory set up an impartial search 2,000 candidate proteins, automated strategy called "high-throughput screening."
Specifically, their task was to comb through a collection or "library" of candidates signaling molecules and testing them one by one to see if anyone could stimulate maturation of immature human TFH cells cultured. the best candidate out of the screen is a secreted protein called activin a member of the family of cytokines.
followed by experiments confirmed that exposure to activin a stimulated immature TFH cells to express genes encoding receptors and other factors typical in mature cells, while the fluorescence microscopy revealed activin a protein in tonsil lymphoid tissues near sites Tfh differentiation has taken place and in close proximity with the cell B. This circumstantial evidence has demonstrated that activin a has was produced in the "right place".
Other comparisons explored and confirmed the rodent / human divergence that had proven to be such an obstacle. The incubation of immature mouse T cells with activin A did not actually encourage their maturation, while the treatment of immature Tfhs macaque monkeys with activin A did.
The discovery of a single primate mechanism is intriguing from an evolutionary point of view, as the biochemical pathways regulating immune activities are often highly conserved in mammals. "Mice are extremely useful in biomedical research in helping us to understand how genes and proteins function," says Crotty. "But from time to time, we see the differences between species, and cell differentiation Tfh was one of those case. "
Finally, the team showed that for activin a boost Tfh maturation, it must activate the DNA-binding molecules called downstream SMAD2 / 3. They discovered this by treating immature TFH cells with the drug Galunisertib, which mutes the SMAD2 signaling, and found that the cells became refractory to activin signals. this experiment not only defined a biochemical pathway, but means that a medicament exists for potentially block T cell "help" keeping the TFH cells in an immature state. - the most obvious application is an autoimmune disease
"Many autoimmune diseases exhibit excessive production of TFH cells, which can lead to the formation of autoreactive antibodies, "explains Michela Locci, Ph.D., lead author of the study and a postdoctoral fellow in the laboratory Crotty. "In at least two of them - the rheumatoid arthritis and systemic lupus erythematosus -. The level of activin A in the blood is higher than normal, suggesting that it contributes to the differentiation Tfh deregulated in these diseases "Locci found these promising associations, but warns that it is too early to say whether Galunisertib, being tested as an anti-cancer drug in clinical trials, could normalize Tfh excess activity in the autoimmune disease.
Overall, the predominant interest Crotty laboratory is in the antibody-based immunity regarding vaccine development. One way that vaccines work is establishing cells B long-term memory when exposed to a recall of deadly pathogen they saw the invader before (albeit in a form of harmless vaccine) and are willing to do antibodies. When TFH cells were discovered in 01, scientists quickly realized that they were necessary for both the development of these memory B cells and instruct them on how to make high affinity antibodies.
"Generating more TFH cells could promote cell more powerful B responses and increase the production of long-term memory cells," says Crotty. "From the standpoint of the design of the vaccine, it may be desirable encourage the development of Tfh cells in vivo since the production of a protective vaccine requires the production of antibodies. "Knowing that activin a is the main source of" encouragement "could lead his laboratory to a new research, this both small molecules potentially useful for transforming activin A on the time of vaccination, instilling more lasting memories in B cells
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