Researchers have detailed a mechanism that sets the stage for the rise of two major subsets of CD4+ T Cells: T follicular helper (TFH) cells and non-T follicular helper (non-TFH) cells. The findings, published in Science, could help in producing better vaccines, helping clinicians fight pathogens, or aid in understanding how to dampen autoimmune disease. The research was done as a collaboration between University of Alabama at Birmingham researchers and colleagues at four other United States institutions.
When activation signals alert the immune system to an infection, TFH cells migrate to the B-cell zones, where they interact with B cells to create germinal centers where they will release high-affinity antibodies. Non-TFH cells, on the other hand, migrate to the site of the pathogen and help by enhancing the function of innate immune cells.
Recent innovations in tracking IL-2 using a gene for green fluorescent protein in reporter mice allowed the research team to distinguish between TFH and non-TFH cells. Testing each group of cells revealed divergent sets of genes induced. Those that produced IL-2 induced genes important for TFH cell development, and cells that did induce IL-2 induced genes for non-TFH cells. This fate determination happens within hours, before cell division of the activated T cells.
When IL-2-producing cells were removed in a second reporter mouse, no TFH cells were produced, but non-TFH cell production continued.
Further experiments to uncover the mechanisms that control early CD4+ T cell differentiation into these cells showed that the percentage of TFH cells correlates with the amount of antigen used to activate naïve CD4+ T cells, as well as the strength with which antigen bound to antigen receptors on the naïve T cells. IL-2 production only occurred in those cells receiving the strongest T-cell receptor signals.
The scientists also found IL-2 production by cells fated to become TFH cells up-regulate a component of the IL-2 receptor that can induce genes for differentiation into non-TFH effector cells. This indicates that IL-2 production can affect IL-2 non-producers by acting in a paracrine fashion.
"The utility of IL-2 as an early marker for cells fated to these different effector programs is established herein," conclude the researchers. "We propose that this should provide a basis for strategies to modulate the balance of effector T cell responses for therapeutic ends."