Anti-CD4 monoclonal antibody, clone wqh40

Persistent antigen exposure in chronic infection and cancer has been proposed to lead to cytotoxic T lymphocyte (CTL) "exhaustion", i.e., loss of effector function and disease control. Recent work identifies a population of poorly differentiated TCF-1(+)PD-1(+)CD8(+)T cells as precursors of the terminally exhausted CTL pool. These "predysfunctional" CTLs are suggested to respond to PD-1 targeted therapy by giving rise to a pool of functional CTLs. Supported by gene expression analyses, we present a model in which lack of CD4(+)T cell help during CD8(+)T cell priming results in the formation of predysfunctional CTLs. Our model implies that predysfunctional CTLs are formed during priming and that the remedy for CTL dysfunction is to provide "help" signals for generation of optimal CTL effectors. We substantiate that this may be achieved by engaging CD4(+)T cells in new CD8(+)T cell priming, or by combined PD-1 blocking and CD27 agonism with available immunotherapeutic antibodies.

Impaired tolerance to innocuous particles during allergic asthma has been linked to increased plasticity of FoxP3(+) regulatory T cells (Tregs) reprogramming into pathogenic effector cells, thus exacerbating airway disease. However, failure of tolerance mechanisms is driven by Th2 inflammatory signals. Therefore, the in vivo role of canonical IL-4 receptor alpha (IL-4R alpha) signaling, an essential driver of Th2-type airway responses to allergens, on the regulatory function of FoxP3(+) Tregs in allergic asthma was explored. Here, we used transgenic Foxp3(cre)IL-4R alpha(-/lox) and littermate control mice to investigate the role of IL-4 and IL-13 signaling via Tregs in house dust mite-induced (HDM-induced) allergic airway disease. We sensitized mice intratracheally on day 0, challenged them on days 6-10, and analyzed airway hyperresponsiveness (AHR), airway inflammation, mucus production, and cellular profile on day 14. In the absence of IL-4R alpha responsiveness on FoxP3(+) Tregs, exacerbated AHR and airway inflammation were shown in HDM-sensitized mice. Interestingly, reduced induction of FoxP3(+) Tregs accompanied increased IL-33 alarmin production and type 2 innate lymphoid cell activation in the lung, exacerbating airway hyperreactivity and lung eosinophilia. Taken together, our findings indicate that IL-4R alpha-unresponsive FoxP3(+) Tregs result in exaggerated innate Th2-type, IL-33-dependent airway inflammation and a break intolerance during allergic asthma.