T follicular helper cells differentiate from Th2 cells in response to helminth antigens

Abstract

The relationship of T follicular helper (TFH) cells to other T helper (Th) subsets is controversial. We find that after helminth infection, or immunization with helminth antigens, reactive lymphoid organs of 4get IL-4/GFP reporter mice contain populations of IL-4/GFP-expressing CD4+ T cells that display the TFH markers CXCR5, PD-1, and ICOS. These TFH cells express the canonical TFH markers BCL6 and IL-21, but also GATA3, the master regulator of Th2 cell differentiation. Consistent with a relationship between Th2 and TFH cells, IL-4 protein production, reported by expression of huCD2 in IL-4 dual reporter (4get/KN2) mice, was a robust marker of TFH cells in LNs responding to helminth antigens. Moreover, the majority of huCD2/IL-4–producing Th cells were found within B cell follicles, consistent with their definition as TFH cells. TFH cell development after immunization failed to occur in mice lacking B cells or CD154. The relationship of TFH cells to the Th2 lineage was confirmed when TFH cells were found to develop from CXCR5− PD-1− IL-4/GFP+ CD4+ T cells after their transfer into naive mice and antigen challenge in vivo.

Human circulating influenza-CD4 + ICOS1 + IL-21 + T cells expand after vaccination, exert helper function, and predict antibody responses

“…Tfh cells have been identified as the CD4 + T cells population specialized in providing help to B lymphocytes in lymph nodes and tonsils (3,9,20). Despite the absence of markers exclusive to this T cells subset (5,6,10,11,21,22), analysis of their phenotype in lymph nodes and tonsils has pointed to a central role of IL-21, CXCR5, and ICOS1 (3,9,12,23). The difficulty in obtaining human samples other than blood, and the recent identification of a migratory counterpart of this T cells population, led us to investigate if antigen-specific CD4 T cells with functional properties of Tfh cells are measurable in peripheral blood, and if the expansion in their number is associated with effective vaccination (12,17).…”

Follicular helper T cells may play an important role in the severity of primary Sjögren's syndrome

“…A recent study demonstrated the ability of T FH cells to form memory cells which differentiate upon recall not only into T FH but conventional helper T cells as well [10]. Furthermore, two elegant studies showed that mouse Th2 and natural regulatory T cells (Treg) may transform into T FH cells under certain in vitro conditions [8,11]. These observations shed light on the developmental plasticity of T FH cells.…”

“…T FH cells were initially proposed as a separate lineage, based on their failure to express T helper (Th) 1 /Th2/Th17 cytokines and lineage-specific transcription factors. Later investigations showed that T FH cells may express characteristic cytokines of canonical helper T effector subsets, including interferon-gamma (IFN-γ), interleukin-4 (IL-4) or IL-17 under specific microenvironment and accordingly, T FH cells seem to be heterogeneous and have a close relationship to Th1, Th2 or Th17 cells [6][7][8][9]. A recent study demonstrated the ability of T FH cells to form memory cells which differentiate upon recall not only into T FH but conventional helper T cells as well [10].…”

Plasticity is the differentiated state of CD4 T cells

“…27 In infections with three different parasites-a nematode, a trematode and a trypanosome-virtually all IL4-secreting CD4 T cells in reactive lymph nodes (either peripheral or mesenteric nodes, depending on route of exposure) had become T FH cells, as defined by the expression of CXCR5, ICOS, PD-1, IL21 and BCL6. [24][25][26] Similar studies have been performed to characterise the plasticity of Th17 cells. 2,3 The tagging technology used in these cases replaced the first exon of the Il17a gene with sequence encoding Cre, intronic sequences and an SV40 polyA tail.…”

“…3 In 2009, the relationship between IL4-producing cells and T FH cells was examined in experiments that simultaneously used two reporters, one targeted to each Il4 allele. [24][25][26] The 4get allele is bicistronic and contains an IRES-EGFP construct after the stop codon of the Il4 gene. It is expressed whenever the Il4 locus is transcribed.…”