Preprint Club
A cross-institutional Journal Club Initiative

Keywords

• Follicular regulatory T cells

• Follicular helper T cell plasticity

• Germinal centre regulation

Main Findings

By leveraging single-cell transcriptomic and T cell receptor (TCR) sequencing, multiplex imaging, flow cytometric and in vitro organoid and cell co-culture techniques, Le Coz and colleagues identified a CD38+ induced T follicular regulatory (iTfr) cell subset in human tonsils that is induced from T follicular helper (Tfh) cells through CD25hi Tfh cell intermediates that upregulate FOXP3 expression. These germinal centre (GC)-resident Tfh-like iTfr cells gain suppressive function while retaining a B-cell helper capability, mediated in part through the production of IL-10 and IL-21. In addition, Tfh-like iTfr cells are spatially, clonally, and functionally distinct from their elite T cell suppressor T regulatory (Treg)-like CD38- natural T follicular regulatory (nTfr) counterparts outside GCs.

Limitations

• The study employed paediatric tonsil samples, and no comparison was made to adult secondary lymphoid tissues likely due to limited sample availability and accessibility. Nevertheless, changes occurring as the immune system matures and evolves in response to antigen exposure over time may result in differences in the frequency, differentiation pathways and/or functional properties of follicular and germinal centre T cells in adulthood – this was not addressed or discussed.

• The use of tonsil wedge dissections facilitated the analysis of clonality and repertoire overlap between regulatory and helper populations of interest achievable with an (understandably) limited sample size; however, the small number of GCs sampled necessarily introduced a selection bias in the cells examined. The results are thus, as the authors acknowledge, limited to clonally-shared cells from the same GCs.

• Tonsil organoids were effectively used; however, additional investigation of organoid structures and cellular locations therein would have strengthened study conclusions.

• Sorting strategies were designed to enable effective separation of key cell subsets of interest, but the sorting strategy adopted precluded examination of CD25- PD1low Tfr cells

• In vitro co-culture models employed GC B cells with Tfr subsets, but they did not include Tfh cells as well. This precluded analysis of functions of Tfr subsets mediated via effects on Tfh cells.

Significance/Novelty

• Provides evidence Tfh cells constitute an alternative source of Tfr cells which retain B cell helper functions in human lymphoid tissues.

• Furthers our understanding of the differentiation pathways and functional localization of two functionally and clonally divergent human Tfr subsets that control GC and follicular outputs.

• Identifies CD38 as a phenotypic marker of helper-like iTfr cells, thereby allowing further mechanistic studies of their dual roles in GC reactions

• Facilitates design of future precision therapies to modulate the iTfr/nTfr balance in disease/vaccine settings

Credit

Reviewed by Quang Nhat Nguyen as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai and the Kennedy Institute of Rheumatology, University of Oxford.