A mouse model to analyze Foxp3+ TFH cells

About This Grant

Protective immunity to many pathogens involves the production of pathogen-specific high-affinity antibody (Ab). Additionally, allergic immune responses often involve the production of allergen-specific high affinity IgE. A unique subset of T cells, follicular helper T (TFH) cells, are required for helping B cells make high affinity Abs. TFH cells promote and control the germinal center reaction. Germinal centers (GCs) and secondary Ab responses cannot develop in the absence of TFH cells, however excessive development of TFH cells can lead to deregulated Ab responses and autoimmunity. A related subpopulation of follicular T cells, T follicular regulatory (TFR) cells are also important for controlling TFH and germinal center responses. Conventional TFR cells develop from Foxp3+ Treg cells. TFR cells have properties of both regulatory T (Treg) cells and TFH cells. Depending on the specific type of immune response, TFR cells can either inhibit the GC and Ab responses or help promote the GC and the Ab response. How these opposite types of TFR functions are regulated is not well understood. Answering the question of how TFR cells are regulated and how they function has become more complex due to the recent discovery of a subclass of TFH cells that up-regulate Foxp3 and express the same markers used to identify TFR cells. These “Foxp3+ TFH cells” appear to be a new subset of TFR cells. However, the function of Foxp3+ TFH cells is not well understood, and their precise role in vivo has not been previously analyzed using a knockout mouse model. In this proposal, we propose to develop a novel mouse model where we will be able to genetically dissect out Foxp3+ TFH cells from the immune response for the first time. Using two different mutant mouse lines, including a newly developed mouse model we have generated, we will produce bone marrow chimeras (BMCs) where TFH and conventional (Treg-derived) TFR (cTFR) cells develop normally but Foxp3+ TFH cells cannot develop. Thus, we can use these mice to probe the development of high affinity Abs in the absence of Foxp3+ TFH cells. This model system can clarify whether Foxp3+ TFH cells have a very different function from cTFR cells in the GC and whether the helper activity of TFR cells for the Ab response in some immune responses is due to cTFR or Foxp3+ TFH cells or both types of cells. IMPACT: this study will generate an innovative mouse model of Foxp3+ TFH deficiency and will validate a new experimental system for analyzing Foxp3+ TFH cells. This work will also provide new information about the regulation of protective Abs and allergic IgE. Our data will hopefully lead to new targets for intervention in allergic and autoimmune disease and new approaches to augmenting protective Ab responses.