Germinal Centers Regulate Human Th2 Development

Abstract

In the present study we demonstrate that all CD4+ T cells in human tonsil expressing the Th2-selective receptor chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) also 1) express high levels of CXCR5, and 2) display a transitional CD45RA/RO phenotype and consistently do not produce significant amounts of cytokines when immediately analyzed ex vivo. Hence, they represent precursors of Th2 effector cells, a conclusion confirmed by their robust production of IL-4, IL-5, and IL-13, but not IFN-γ, after in vitro activation. CD4+ T cells, which express only intermediate levels of CXCR5, instead develop into IFN-γ-producing cells under identical culture conditions, thus establishing a correlation between relative levels of CXCR5 expression and the acquired cytokine profile. Because CXCR5 is critically involved in follicular localization, the results suggest that these CRTH2+ Th2 cells preferentially develop their cytokine-producing phenotype within germinal centers (GCs), whereas extrafollicular differentiation instead promotes Th1 development. In support for this proposal, we show that T cells with an intermediate expression of CXCR5 can be forced to also produce IL-4 and IL-13 if cultured with allogenic GC B cells. Finally, we demonstrate that the previously described CD57+ GC T cells also express high levels of CXCR5 but instead of comprising a Th2 precursor, they represent anergized T cells. Taken together, these data suggest that GCs and B cells regulate CD4+ T cell differentiation in a finely tuned fashion, either by promoting differentiation of Th2 cells, which apparently leave the lymphoid tissue before evolving a cytokine-producing phenotype, or by furnishing T cell unresponsiveness.

Multiple checkpoints keep follicular helper T cells under control to prevent autoimmunity

“…Tfh cells also express high amounts of the tumour-necrosis factor receptor superfamily, member 6 (Fas), and are more sensitive to cell death after TCR stimulation than naïve or memory helper T cells. 50,51 Histological staining reveals that, unlike interfollicular T cells, human tonsillar Tfh cells do not express Bcl2, 52 which is consistent with the reported role for the Tfh-directing transcription factor Bcl6 in repressing Bcl2 expression. 53 Overexpression of Bcl2 in the entire hematopoietic compartment (Bcl2 transgene controlled by Vav gene regulatory sequences) instead of selectively in B cells (Bcl2 transgene controlled by an IgH enhancer), results in spontaneous germinal centre formation.…”

Abatacept Limits Breach of Self-Tolerance in a Murine Model of Arthritis via Effects on the Generation of T Follicular Helper Cells

“…Although CTLA-4Ig was demonstrated to reduce serum IL-17 during collagen-induced arthritis (43), this is the first study to show a direct inhibition of Ag-specific T cell IL-17 production by abatacept. Interestingly, IL-13 was shown to be produced by TFH cells in human tonsils (44), and this was significantly reduced by treatment with abatacept.…”

T Follicular Helper, but Not Th1, Cell Differentiation in the Absence of Conventional Dendritic Cells

“…Therefore, the reduced expression of T-bet in the absence of cDCs does not appear to result in the activation of an endogenous Th2 differentiation program, which is the consequence of T-bet deficiency after Toxoplasma gondii infection (53). Still, in light of the close relationship between Tfh and Th2 effector cells (54)(55)(56), the accessory role cDCs play in balancing Th2 effector versus Tfh cell commitment cannot be extrapolated from the present results with a strong Th1-polarizing adjuvant and clearly needs further investigation.…”