ICOSL, OX40L, and CD30L Control Persistence of Asthmatic CD4 Trm cells.

Abstract

Background: Tissue-resident memory CD4 T cells (Trm) are linked to asthma exacerbations and being able to reduce their frequency or activity has implications for clinical therapy.

Objective: To find costimulatory molecules that control the reactivation of allergen-induced memory CD4 T cells and determine if their targeting alters the longevity of lung localizing memory T cell populations associated with asthma.

Methods: Transcriptomic profiles of human and mouse asthmatic lung CD4 T cells were studied to identify potentially active costimulatory molecules, and the effect of blocking these molecules was examined in a model of disease exacerbation.

Results: ScRNA-seq of allergen-responding lung CD4 T cells from asthma patients revealed expression of the costimulatory molecules ICOS, TNFRSF4 (OX40), and TNFSF8 (CD30L). In a murine model of allergic asthma exacerbations, scRNA-seq similarly demonstrated expression of Icos, Tnfrsf4, and Tnfsf8 in responding memory effector CD4 T cells even though many inflammatory subpopulations were induced in the lungs. Therapeutically inhibiting OX40L with CD30L in vivo partially suppressed the recall exacerbation response to allergen, but neutralizing ICOSL with OX40L or CD30L efficiently limited the accumulation of lung-localized memory effector T cells and ablated all aspects of lung inflammation. Importantly, transient therapeutic inhibition of these molecules together resulted in greatly reduced numbers and activity of tissue-resident memory CD4 T cells maintained in the lungs over time, even when mice were further challenged repeatedly with allergen. This led to a state of hyporesponsiveness such that subsequent exposure to allergen failed to re-exacerbate asthmatic lung tissue inflammation.

Conclusion: Combined inhibition of ICOSL with OX40L or CD30L limits the continued accumulation of large populations of inflammatory lung tissue-resident memory CD4 T cells, revealing therapeutic treatments applicable for asthma.