T Follicular Helper Cells Have Distinct Modes of Migration and Molecular Signatures in Naive and Memory Immune Responses

Abstract

B helper follicular T (Tfh) cells are critical for long-term humoral immunity. However, it remains unclear how these cells are recruited and contribute to secondary immune responses. Here we show that primary Tfh cells segregate into follicular mantle (FM) and germinal center (GC) subpopulations that display distinct gene expression signatures. Restriction of the primary Tfh cell subpopulation in the GC was mediated by downregulation of chemotactic receptor EBI2. Following collapse of the GC, memory T cells persisted in the outer follicle where they scanned CD169(+) subcapsular sinus macrophages. Reactivation and intrafollicular expansion of these follicular memory T cells in the subcapsular region was followed by their extrafollicular dissemination via the lymphatic flow. These data suggest that Tfh cells integrate their antigen-experience history to focus T cell help within the GC during primary responses but act rapidly to provide systemic T cell help after re-exposure to the antigen.

Peripheral T Follicular Helper Cells Are the Major HIV Reservoir within Central Memory CD4 T Cells in Peripheral Blood from Chronically HIV-Infected Individuals on Combination Antiretroviral Therapy

“…High expression of CCR7 on pTfh cells suggests that they may traffic to sec- ondary lymphoid organs, possibly upon antigen encounter (24). New findings also support the concept that LN Tfh cells can exit into the circulation after becoming memory cells (42). However, the association of pTfh cells with HIV reservoirs in the context of cART and the susceptibility of pTfh cells to HIV infection are currently unknown.…”

A distinct subpopulation of CD25−T-follicular regulatory cells localizes in the germinal centers

“…As such, CD25 − Tfr cells are best thought of as a mature stage of Tfr differentiation that is enriched for, but not necessarily made entirely of, cells in the GC. This caveat may also be the case with current strategies used to separate Tfh cells from GC-Tfh cells, with the CXCR5 hi PD1 hi BCL6 hi phenotype associated with GC-Tfh cells being enriched for, but not exclusive to, GC localized cells, as confirmed by several microscopy studies (18,40). Additionally, GC-Tfh cells are capable of cycling in and out of the GCs, so they may not be localized in the GC at all times (18).…”

T Cell/B Cell Collaboration and Autoimmunity: An Intimate Relationship

“…The GWAS data also highlight Gpr183 , the gene encoding the 7α,25-dihydroxycholesterol receptor EBI-2, which must be downregulated for appropriate B cell positioning in GC (116, 117). Indeed forced expression of EBI-2 was shown to diminish the GC response and instead direct B cells to extrafollicular sites (117) while transduction of T cells with an EBI-2 expression vector impaired their capacity to localize to GC (118). Another gene product associated with autoimmunity in this dataset is SLAMF6, which co-operates with SAP to promote T cell/B cell adhesion and is essential for formation of functional GC (119).…”