Biology subjects

Harker, J. A.

Publications and source records attributed to Harker, J. A..

2 recordsLinked to original sources

bioRxiv2025

Differentiation of human T follicular helper cells in vitro requires co-operation between STAT3 and SMAD signaling cytokines that is restrained by IL-2

T follicular helper cells (TFH) are a CD4 T cell subset required for effective humoral immunity; promoting antibody responses to vaccines and natural infections. The mechanisms by which human TFH differentiate are not fully understood, and given the anatomical localization to the secondary lymphoid tissues, and asynchronous nature of in vivo TFH populations, studying TFH differentiation in vitro represents an attractive alternative, through which the mechanisms which govern TFH differentiation can be explored. Here we demonstrate reliable differentiation of in vitro TFH from naive human CD4 T cells in a STAT3 dependent fashion. Cooperation between STAT3 and SMAD signaling cytokines led to expression of the lineage defining transcriptional regulator BCL6, multiple downstream proteins required for TFH function and localization (including PD1 and CXCR5), and potent IL-21 production capacity by these in vitro TFH. Critically we found that autocrine production of IL-2 acted as an intrinsic brake on TFH differentiation in vitro; promoting proliferation but limiting the acquisition of a TFH phenotype resembling that found in germinal centers in vivo; neutralization of IL-2 resulting in the emergence of this phenotype. Overall, we show that human TFH expansion, differentiation and function relies on careful regulation of pro- and anti-TFH cytokine signaling.

immunology↗

bioRxiv2018

Therapeutic ICOS blockade reduces T follicular helper cells and improves allergic airway disease

Allergic asthma is a disease of chronic airway inflammation and remodelling, characterised by a dysregulated type 2 response and allergen-specific IgE. T follicular helper cells (TFH) are critical to antibody production and have recently been implicated in allergic airway disease (AAD) pathogenesis. The role of TFH in established disease and the therapeutic potential of targeting them are however not fully understood. Using two aeroallergen driven murine models of chronic AAD, TFH were first identified in the lung draining lymph nodes but with prolonged exposure were present in the lung itself. Sustained allergen exposure led to the accumulation of TFH, and concomitant development of germinal centre B cells. Blockade of Inducible T cell co-stimulator (ICOS) signalling during established AAD depleted TFH without adversely affecting the differentiation of other CD4+ T cell subsets. This resulted in impaired germinal centre responses, reduced allergen specific IgE and ameliorated inflammation and airway hyper-responsiveness, including reduced pulmonary IL-13. TFH did not however appear to produce IL-13 directly, suggesting they indirectly promote type-2 inflammation in the lungs. These data show that TFH play a pivotal role in the regulation of AAD and that targeting the ICOS-L pathway could represent a novel therapeutic approach in this disease.

immunology↗