Anti-Icos Monoclonal antibody, clone D409.5B [FITC]

Regulatory T cells (Tregs) are required for the maintenance of immune tolerance and adoptive Treg infusion therapy has become a promising approach to suppress immune responses in diseases such as autoimmunity and transplant rejection. However, one critical challenge of Treg therapy is the requirement of in vitro expansion of functionally stable Tregs while preventing either the contamination of T effector and/or emergence of unstable pathogenic Tregs. Recent studies showing distinct metabolic requirements of T effectors and Tregs suggest that manipulation of cell metabolism may be an attractive strategy to achieve this goal. Here we show that human thymically derived Tregs (tTregs) and in vitro induced Tregs (iTregs) from naive T cells engage glycolysis equivalently upon activation. However, inhibiting glucose metabolism via 2-deoxy-D-glucose (2DG) has distinct effects on each of these subsets. While 2DG treatment at the onset of activation significantly reduced the proliferation and expression of suppressive molecules such as ICOS and CTLA-4 in tTregs, its effect on FOXP3 expression was small. In contrast, 2DG treatment during iTreg induction modestly decreased their proliferation but strongly reduced both ICOS and FOXP3 expression. Importantly, both Treg subsets became insensitive to 2DG after day 3 post activation with little effect on either proliferation or FOXP3 expression while T conventional Th0 cells showed reduced proliferation under the same conditions. Moreover, 2DG treatment at day 3 did not impair the suppressive capabilities of Treg subsets. Collectively, these findings suggest that there is a distinct temporal requirement of glycolysis in each of the activated human Treg subsets and T conventional cells. Furthermore, 2DG treatment at the onset as a strategy to impair contaminating T effector cell proliferation is unfavorable for optimal Treg generation as well.

Background Allergic asthma is characterized by chronic inflammation and remodelling of the airways, associated with dysregulated type 2 immune responses and allergen-specific IgE. T follicular helper cells (T-FH) are crucial in T-dependent B-cell responses and have been implicated in allergic airway disease (AAD). T-FH, unlike other CD4(+) T cells, are uniquely reliant on continuous ICOS signalling to maintain their phenotype after T-cell priming; therefore, disrupting this signal can impair T-FH responses. However, the contribution of T-FH to disease during chronic aero-allergen exposure and the therapeutic potential of targeting these cells have not been evaluated. Methods To establish AAD, female BALB/c mice were repeatedly exposed to house dust mite or Alternaria alternata three times a week for up to 5 weeks. To examine the impact of T-FH on AAD, mice were allergen exposed for 5 weeks and co-administered anti-ICOS Ligand-targeted antibodies, three times a week for the last 2 weeks. Results T-FH were first observed in the lung-draining lymph nodes and with further exposure were also found locally within the lungs. T-FH accumulated with sustained allergen exposure, alongside germinal centre (GC) B cells. Blockade of ICOS signalling after AAD establishment successfully depleted T-FH but did not affect the differentiation of other CD4(+) T-cell subsets. This reduced GC responses, allergen-specific IgE, inflammation, pulmonary IL-13 and airway hyper-responsiveness. Conclusions T-FH are crucial in the regulation of AAD and the ICOS/ICOS-L pathway could represent a novel therapeutic target in allergic asthma.