**5. The Inhibition of Anaphylactic TfH Cells: A Novel Role for IL-13 Neutralisation**

Very recently, the paradigm in IL-4/IL-13 immune function in the germinal centre reaction was that IL-4 is central to germinal centre-based affinity maturation, as well as isotype switching toward IgE of B-cells, but not IL-13, through follicular T-helper (TfH) 2 cells characterised by IL-4 secretion (reviewed in [60]). However, a very recent landmark study identified a new Tfh subset characterised by IL-13 secretion which is responsible for the generation of IgEhigh B cells in response to stimulation with allergens [61] (Figure 2). Crucially, TfH13 cells were not only identified in the newly created hyper-IgE-harbouring mouse model, but also detectable and increased in humans with peanut allergy. Importantly, TfH13 cells did not drive IgEhigh B cell and peripheral IgE production in response to parasitic (helminth) infection but only in response to anaphylactoid allergen challenge (also reviewed in [62]). Moreover, T cell-specific ablation of IL-13 was found to profoundly suppress IgE synthesis. These data suggest that elimination of IL-13 function may lead to suppression of anaphylactic reaction to a wide range of allergens.

As detailed above, the response to such therapeutic intervention may profoundly differ between anti-IL-13 MAb administration and anti-IL-13 vaccination, in particular since the latter is expected to induce IL-13-targeted memory clones (both B and T cells), which could modulate the germinal centre reaction by cytokine secretion and which would not feature in MAb-mediated IL-13 suppression. In addition, it is intriguing that TfH1 cells, which would mediate class switching in response to a VLP-type vaccine, would be instrumentalised in this way to suppress the activity of TfH13 cells. In fact, this concept appears to already have been validated for TfH2 cells, since blocking of IL-4 caused a profound block in Th2-class switch and improved antibody responses to oxycodone and diptheria-pertussis-tetanus vaccination [64]. Clinically, it is very possible that the routinely observed major drop in serum IgE levels in patients treated with dupilumab is in part mediated by suppression of TfH2 cells. It would therefore be of interest to compare the performance of monoclonal- vs. vaccine-mediated IL-13 inhibition in the novel DOCK8-/- mouse model established in the above cited

study. Moreover, given the different mode of action of a polyclonal response, combined with the novel anti-TfH13 mode of action, it is entirely possible that VLP vaccine-based IL-13 targeting will perform different to MAb-based treatment in allergic asthma.

**Figure 2.** Function of IL-13-dependent TfH cells in IgE production in response to allergens. Simplified schematic showing the light zone of a peripheral lymphoid germinal centre (GC) where a naïve IgM-positive B cell survives apoptosis after antigen (Ag) encounter presented by a follicular dendritic cell (FDC). Prior and additional interaction with Th cells are not shown. Depending on the type of antigen, the B cell may then receive stimulation by TfH1 cells, resulting in class switching to Ig-isoforms, as indicated. Further, sequential stimulation by TfH2 cells may cause secondary class switching to IgG4 or IgElow phenotypes. Finally, the newly identified IL-13-dependent TfH13 cells, may cause tertiary switching to IgEhigh in the context of allergen stimulation. The schematic is based on figures in [61,63].
