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Immune "trainer" cells committed and long-lived, researchers find

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Quinn Eastman

When the immune system is responding to an infection or a vaccine, follicular helper T cells (Tfh cells) provide signals critical for the formation of germinal centers and the generation of potent antibodies.

Researchers led by Emory's Rafi Ahmed show that Tfh cells are committed and long-lived -- contrary to other reports that their appearance is only transient. In this image of a lymph node, Tfh cells are the red cells in areas where they are surrounded by blue.

Researchers at Emory Vaccine Center have demonstrated that follicular helper T cells, important for generating potent antibodies, maintain their character even after a viral infection is over.

Antibodies are proteins produced by the immune system that can block or neutralize a virus. Follicular helper T cells are essential for long-lived B cell responses that generate the antibodies that serve as the basis for most effective vaccines. Understanding how follicular helper T cells form and are maintained could improve the design of vaccines against a wide variety of viruses, such as HIV or influenza.

The results were published this week in the journal Immunity.

When the immune system is challenged – either by infection or by a vaccine – specialized structures form in the lymph nodes and spleen called germinal centers. Germinal centers resemble competitive “training academies” for B cells, which produce antibodies against the virus or vaccine. In germinal centers, B cells that make high-quality antibodies survive, while other B cells die.

Follicular helper T (Tfh) cells are, in this analogy, the drill sergeants. They provide signals critical for the formation of germinal centers and the selection of B cells.
Without these signals from Tfh cells, B cells are unable to generate high quality antibodies and do not differentiate properly to be able to produce antibodies over very long periods of time.

“Right now there is a lot of confusion in the field about Tfh cells, and the assumption that many are making is that after the clearance of antigen, Tfh cells either die or do not maintain their identity as Tfh cells,” says first author J. Scott Hale, PhD. Hale is a postdoctoral fellow in the laboratory of Emory Vaccine Center director Rafi Ahmed, a professor of microbiology and immunology at Emory and a Georgia Research Alliance Eminent Scholar.

“Our study shows that after antigen clearance, the Tfh cells become memory cells and maintain some aspects of their lineage-specific gene expression signature.  Importantly, these Tfh memory cells are ready to respond rapidly as Tfh cells after reinfection, allowing them to quickly help B cells again.”

Hale and his colleagues studied the immune responses of mice to LCMV (lymphocytic choriomeningitis virus) infection. They followed T cells that had been genetically engineered to be reactive against LCMV and then transferred into fresh mice before LCMV infection.

Tfh cells are distinguished by a marker on their surfaces, CXCR5, which is a “pass” to the B cell areas of lymph nodes and germinal centers. Hale and his colleagues found that during LCMV infection, some virus-specific T cells acquire CXCR5 and other Tfh markers. Three months later, long after the infection is over, a fraction of T cells keep CXCR5 but lose the other surface markers. These cells still have a pattern of genes turned on that is similar to the signature of activated Tfh cells, the Emory team found.

Next, researchers took “memory” Tfh cells – long-lived cells that had already responded to LCMV infection and had acquired CXCR5 – transferred them into fresh mice and challenged those mice with a new viral infection.

The result: upon infection, the memory cells became Tfh cells again. Once they’ve made the decision to become Tfh cells, the cells are “locked in” and can’t turn on genes that are activated in other types of T cells, the researchers found.

Hale says immunologists are still figuring out the best ways to design a vaccine so that it will stimulate Tfh cells.

“This is extremely important when we think about prime-and-boost [two or more shots] immunization strategies,” he says. “If we can devise strategies that will optimize the generation of Tfh memory cells, that will be a key to better antibody responses. In particular, there may be ways to improve broadly neutralizing antibody responses to HIV antigens following immunization, or to boost responses against specific epitopes to make universal influenza vaccines.”

The research was supported by the National Institute of Allergy and Infectious Diseases. P01 AI080192, R01 AI030048, and F32 A1096709.

Reference: J.S. Hale, B. Youngblood, D.R. Latner, A.U.R. Mohammed, L. Ye, R.S. Akondy, T. Wu. S.S. Iyer and R. Ahmed. Distinct Memory CD4+ T Cells with Commitment to T Follicular Helper- and T Helper 1-Cell Lineages Are Generated after Acute Viral Infection. Immunity (2013).      

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