ICOSL, OX40L, and CD30L Control Persistence of Asthmatic CD4 Trm Cells

Tissue-resident memory T cells (Trm) are central to maintaining autoimmune and inflammatory disease. Modulation of their continued replenishment in tissues has significant implications for clinical treatment. In a murine model of lung inflammation, scRNA-seq revealed the complexity of antigen-responding CD4+ Trm, encompassing many pathogenic subpopulations including Th2, Th17, Th1 and CTL, but suggested several targets for therapeutic intervention, with significant co-expression of the costimulatory molecules OX40, ICOS, CD30, and CD30L throughout these T cells. Inhibiting ICOSL alone, or co-blocking OX40L and CD30L, with neutralizing antibodies, only partially suppressed the response of Trm to recall antigen, whereas inhibiting all three molecules strongly reduced the accumulation of Trm-derived effector memory T cells, and ablated all aspects of lung inflammation. Most importantly, transient therapeutic inhibition of these molecules together prevented the continued accumulation and long-term persistence of induced Trm, leading to a state of tolerance such that subsequent exposure to antigen failed to re-establish a pathogenic inflammatory response. These data show that costimulatory molecules are critical for reactivation and persistence of pathogenic CD4+ Trm, and reveal several therapeutic combinations that are applicable for treatment of lung inflammatory disease and potentially multiple autoimmune diseases.