Nonbinary Roles for T Follicular Helper Cells and T Follicular Regulatory Cells in the Germinal Center Response

Development of high-affinity Abs in the germinal center (GC) is dependent on a specialized subset of T cells called "T follicular helper" (TFH) cells that help select Ag-specific B cells. A second T cell subset, T follicular regulatory (TFR) cells, can act as repressors of the GC and Ab response but can also provide a helper function for GC B cells in some contexts. Recent studies showed that, apart from their traditional helper role, TFH cells can also act as repressors of the Ab response, particularly for IgE responses. We review how both TFH and TFR cells express helper and repressor factors that coordinately regulate the Ab response and how the line between these two subsets is less clear than initially thought. Thus, TFH and TFR cells are interconnected and have "nonbinary" functions. However, many questions remain about how these critical cells control the Ab response.