| The effector subset of CD4 T cells that is responsible for mediating T-dependent antibody responses has been classified as follicular helper T cells (TFH cells). TFH cells, defined by expression of the surface markers CXCR5, PD-1 and ICOS, are located in germinal centers where they provide help for B cell maturation through the secretion of IL-21 and expression of CD4OL; however the transcription factor that is required for their development is unknown. The transcriptional repressor Bcl6 is upregulated in TFH cells, yet the role that it plays in TFH cells has not been described. We have found downregulation of P-selectin glycoprotein ligand-1 (PSGL1) as a new surface marker for TFH cells, and show that Bcl6 is required for the development of TFH cells that are PSGL1lo. Activated antigen-specific CD4 PSGL1lo T cells are enriched for expression of CXCR5 and PD-1, and highly upregulate IL-21 and Bcl6. In addition, we find that Bcl6 is required in CD4 T cells for development of germinal centers, presumably because TFH cells are required for their formation or development. Over-expression of Bcl6 leads to an increase in PSGL1lo TFH cells; however, it cannot rescue TFH cell development in the absence of ICOS. Consistent with others, we find B cells are required for full development of TFH cells, but not for downregulation of PSGL1, suggesting there are multiple steps in development of the subset. These data demonstrate that Bcl6, independent of ICOS signaling, is critical for the development of this lineage. We also show that TFH cells are not limited to secreting IL-21, as activated CD4 T cells that express the TFH cell surface markers CXCR5, PD-1 and are PSGL1lo can also make IFN-gamma or IL-4. In addition, subsets of TFH cells located in the germinal center are positive for IFN-gamma or IL-4. This challenges the model that TFH cells are incapable of secreting cytokines associated with other CD4 T cell subsets, and suggests an alternative model in which some plasticity exists. This work has significantly contributed to our understanding of TFH cell development, and has identified a new marker that may have functional relevance to the TFH cell population. |
