CD4 T cells are major immune cell types that mediate effector responses appropriate for diverse incoming threats. These cells have been categorized into different subsets based on how they are induced, expression of specific master transcription factors, and the resulting effector cell phenotypes as defined by expression of signature cytokines. However, recent studies assessing the expression of gene modules in single CD4 T cells, rather than expression of one or a few signature genes, have provided a more complex picture in which the canonical model does not fit as cleanly as proposed. Here, we review the concepts of lineage commitment, plasticity and functional heterogeneity in the context of this greater complexity. We then apply our current understanding of CD4 T cell subsets to discuss outstanding questions regarding follicular helper T cells and follicular regulatory T cells with respect to their shared features with other known CD4 T cell subsets.
Keywords: CD4 T helper cell subsets; Follicular helper T cells; Follicular regulatory T cells; Gene modules; Gene regulatory networks; Single-cell genomics; T cell differentiation; T cell heterogeneity; T cell plasticity; Th17 cells.
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