T follicular helper cell heterogeneity: Time, space, and function

Abstract

Summary T follicular helper (Tfh) cells play a crucial role in orchestrating the humoral arm of adaptive immune responses. Mature Tfh cells localize to follicles in secondary lymphoid organs (SLOs) where they provide help to B cells in germinal centers (GCs) to facilitate immunoglobulin affinity maturation, class‐switch recombination, and generation of long‐lived plasma cells and memory B cells. Beyond the canonical GC Tfh cells, it has been increasingly appreciated that the Tfh phenotype is highly diverse and dynamic. As naive CD4+ T cells progressively differentiate into Tfh cells, they migrate through a variety of microanatomical locations to obtain signals from other cell types, which in turn alters their phenotypic and functional profiles. We herein review the heterogeneity of Tfh cells marked by the dynamic phenotypic changes accompanying their developmental program. Focusing on the various locations where Tfh and Tfh‐like cells are found, we highlight their diverse states of differentiation. Recognition of Tfh cell heterogeneity has important implications for understanding the nature of T helper cell identity specification, especially the plasticity of the Tfh cells and their ontogeny as related to conventional T helper subsets.

Establishment of normative ranges of the healthy human immune system with comprehensive polychromatic flow cytometry profiling

“…Aberrant Tfh responses have been associated with autoimmune diseases, and in vaccine studies, Tfh cells are monitored as a potential marker of vaccine immunogenicity. Since Tfh cells were missing in the original Th subset panel, we included reference ranges for Tfh cells and its subsets from an internally developed 12-color T follicular helper cell (Tfh) panel constructed using common Tfh markers [11][12][13]. Though not a HIPC proposed panel, we developed a Tfh panel that will support ongoing research in the field and captures blood memory Tfh cells and follicular regulatory (Tfr) T cells, along with the characterization of activation state and Tfh subset [14,15].…”

Human follicular helper T cell promoter connectomes reveal novel genes and regulatory elements at SLE GWAS loci

“…An important inflammatory leukocyte required for the development of SLE is the follicular helper T cell (TFH). TFH differentiate from naïve CD4+ T cells in the lymph nodes, spleen, and tonsil, where they license B cells to produce high affinity protective or pathogenic antibodies 5, 6 . Given the central role for TFH in the regulation of humoral immune responses, genetic susceptibility to SLE is highly likely to manifest functionally in this immune cell population.…”

Immune metabolism regulation of the germinal center response

“…Upon TCR activation by cognate antigen on antigen-presenting DCs, naive T cells differentiate into pre-T FH cells in the T-cell zone of secondary lymph organs. Pre-T FH cells then migrate toward B-cell follicles where the subsequent GC reaction develops 28 (Fig. 2).…”

“…Moreover, mTORC1 activation has been linked to the expansion of autoreactive T FH cells by promoting the translation of Bcl6 in the Def6 tr/tr Swap70 −/− DKO mice 37 . This nuanced mode of metabolic reprogramming may be due to an adaptation of T FH cell differentiation to a unique niche of nutrient consumption that allows them to survive in a relatively nutrient-deficient environment, including oxygen 28 .…”