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Key step in the transformation of B-cells to antibody-secreting cells described

Posted: 8 May 2019 | | No comments yet

Scientists have detailed the role of a key controlling factor in the transformation of B-cells into antibody-secreting cells.

This has been detailed by immunologist Frances Lund, PhD, and colleagues. “Despite the important role the antibody-producing B lymphocytes play both in protection from infection and in autoimmunity, we know remarkably little about these B-cells,” said Lund, of the research, which is published in the journal Immunity. “This basic study shows that specific inflammatory signals regulate both the development and maintenance of the antibody-producing B-cells.”

Antibody-secreting cells are the cells that produce antibodies to fight invading pathogens like viruses. The key controlling factor is needed for memory B-cells to respond to a second, subsequent infection by a pathogen.

“This finding has important practical implications as we might be able, someday, to manipulate these inflammatory signals to increase antibody-producing B-cell responses following vaccination or suppress the inflammatory signals to decrease antibody responses in the setting of autoimmune disease,” continued Lund, who is professor and chair of the University of Alabama at Birmingham Department of Microbiology, in the UAB School of Medicine.

The immune system includes B and T lymphocytes that produce factors to protect the body from pathogens. The B lymphocyte produces antibodies, which bind to viruses and bacteria and target those pathogens for elimination. B lymphocytes, or B-cells, have to go through a developmental change as they transform from B-cells to antibody-secreting cells. Key control points for this differentiation in B-cells, or other immune cells, are transcription factors.

Lund and colleagues at UAB, Emory University, the University of California-San Diego and the University of Rochester looked at the function of one transcription factor, T-bet. In T lymphocyte cells, which are needed to help induce the B-cell immune response, T-bet regulates the activation, proliferation, differentiation, lifespan and effector functions of those immune cells. Yet little was known about whether T-bet could also influence B-cell fate decisions.

A series of experiments by Lund’s team have shown that T-bet does play an important role in B-cells after they are activated by T helper-1 cells. However, the researchers found that T-bet in the B cells acts through a mechanism greatly different from that of T-bet in T-cells.

Study findings

In T-cell development, T-bet activates inflammatory gene programmes that allow the T-cells to become T helper-1, or Th1, cells that can kill viruses and bacteria. The Th1 cells can also ‘help’ B-cells by producing an inflammatory cytokine called interferon-gamma, which programmes the B-cells to express T-bet and also promotes the transformation of the B-cells into antibody-secreting cells.

Surprisingly, unlike T-cells, where T-bet turns on the inflammatory gene program, T-bet repressed or turned off more than 2,000 genes in the Th1-activated B-cells. Many of the genes that are repressed by T-bet in B-cells are normally involved in antiviral and inflammatory activity.

The researchers found that the expression of the inflammatory gene programme in B-cells prevents the B-cells from differentiating into antibody-secreting cells. In fact, B-cells that have a genetic mutation and are unable to efficiently express T-bet are transformed into inflammatory effector cells following activation with Th1 cells. However, these T-bet-deficient B-cells fail to develop into antibody-secreting cells.

In accompanying experiments using influenza virus-infected mice, the Lund team found that B-cell intrinsic T-bet expression was required for the development of influenza-specific long-lived antibody-secreting cells, which provide protection from subsequent encounters with the virus.

T-bet was also required for differentiation of the influenza-specific memory B-cell into antibody-secreting cells following an influenza challenge-infection in mice. Therefore, T-bet-expressing B-cells play an important role in protecting the body from viral infections.

Although influenza infection causes T helper-1 cells to produce interferon-gamma and promote up-regulation of T-bet by the B-cells and their differentiation into antibody secreting cells, not all pathogens induce T helper-1 cell development. However, for T helper-2-induced B-cell response, the researchers found that T-bet was not required for B-cell differentiation into antibody-secreting cells.

Therefore, the researchers say that T-bet is not a core transcription factor required for antibody-secreting cell commitment in all settings. Rather, T-bet acts to prevent B-cells from assuming an alternate inflammatory effector cell fate in response to interferon-gamma, the cytokine that is produced in response to some, but not all, pathogens and auto-antigens.

 

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