Our body can remember specific pathogens and other foreign substances (antigens) years after the first encounter. B cells, the type of lymphocytes that produce antibodies, are one of the key players for the establishment of this long-term memory. Upon activation, B cells proliferate and give rise to antibody-secreting plasma cells (PCs) or memory B cells (Bmems). The Bmems persist in the body and are poised to respond rapidly and with a high intensity by proliferating and differentiating into new PCs following subsequent exposures to the antigen.  The longevity of the Bmems and the strength of their response are the basis of an adequate antibody-mediated immune response following infection and a successful vaccination. The mechanisms for the establishment of long-lived Bmems and the induction of recall responses are not well understood.   In a recent study published in Nature Immunology, Takatsuka and colleagues (2018) embarked on a journey to look for new insights into these important mechanisms.

During the antibody-mediated immune response to certain antigens, the fate of the proliferating B cells is determined by a group of T lymphocytes called helper T cells. Those T cells provide “help” to the B cells through physical interactions, but also via secretion of functional molecules, known as cytokines. The cytokines bind to their receptors (expressed on B cells) and induce intracellular signals that result in biological changes in the B cells. Various cytokines including interleukin -21 and -4 (IL-21 and IL-4) are known to be crucial for the generation of different types of B cells and secretion of specific antibodies. However, the contribution of those cytokines to the development and function of memory B cells remains contentious. In this study, researchers focused on interleukin-9 (IL-9) and its receptor IL-9R, which they found to be selectively expressed on Bmems compared to B cells that have never encountered antigen (naïve B cells).

Takatsuka and colleagues investigated the importance of IL-9R signaling in B cells.  They showed that upon stimulation with IL-9 in vitro, B cells do not divide well if they lack the IL-9R. Also, mice that lack both copies of the IL-9R gene (il-9r ^–/ ^– mutant mice) can elicit antigen-specific antibody production and development of Bmems, but they fail to stimulate those memory cells during a second encounter. Several years after a vaccination or a first infection, when the primary antibody response has faded away, the body relies on memory B cells and their activation to fight against subsequent infections. This recall response requires signaling through IL-9R. Therefore, this pathway may influence how long antibody-mediated immunity can last following infection or immunization.

Activated B cells can also enter the germinal centers, which are specialized structures formed by mature B cells within secondary lymphoid organs such as lymph nodes and spleens, instead of developing into PCs or Bmems. In the germinal center, the mature B cells divide very rapidly and undergo a multitude of gene mutations (somatic hypermutation).  The goal of these expansions and mutations is to produce antibodies that have a very high affinity to a specific antigen (affinity maturation). This germinal center reaction is critical for the efficacy of the natural or vaccine-induced humoral immunity against pathogens. While the researchers here did not find any difference in development and maintenance of Bmems between wild-type mice and il -9r ^–/ ^– mutant mice following immunization, they did observe that in the absence of IL-9R, activated B cells are more prone to enter the germinal center reaction.

Previous studies have demonstrated that IL-9 was produced by different subsets of helper T cells such as Th9 and T follicular helper cells (Tfh, which resides in the follicles of secondary lymphoid organs and provide help to activated B cells), and some innate immune cells such as mast cells and innate lymphoid cells. Since they were studying a T-dependent antigen, they assumed that during the recall response helper T cells (which are now also memory cells) would be producing IL-9. Surprisingly, they found that IL-9 was mostly expressed by the Bmems and not by the Tfh, and the expression of IL-9 in the Bmems was increased during the recall response. This suggests that Bmems might be activating IL-9R by secreting IL-9, and this might be a feedback mechanism where the memory B cells may regulate their own expansion and differentiation upon stimulation.

In this paper, Takatsuka’s group sheds light on a new regulatory mechanism for memory B cells and a potential pathway that can be utilized during design of vaccines to control their effects.  They demonstrated that IL-9/IL-9R signaling facilitates early proliferation of Bmems and their differentiation into antibody-producing plasma cells upon re-exposure to an antigen. This is important for sustained and long-lived humoral immunity following natural infection or a single dose-vaccination. IL-9/IL-9R signaling can be over-activated to boost antibody production, however, they discovered that the same pathway tends to downregulate the germinal center reaction through an autocrine or paracrine stimulation. This last observation suggests that in the case of multi-dose vaccine, IL-9/IL-9R signaling can be controlled to promote somatic hypermutation and affinity maturation at the expense of more antibody production and induce a highly effective humoral immune response.

Reference: 

Takatsuka, S. et al. IL-9 receptor signaling in memory B cells regulates humoral recall responses. Nature Immunology 19, 1025-1034 (2018). doi: 10.1038/s41590-018-0177-0

Souwelimatou Amadou Amani is a third year graduate student in Microbiology and Immunology  at the University of Oklahoma Health Sciences Center. Her research focuses the dynamics of humoral immunity to Clostridium difficile infection.