Instructor La Jolla Institute for Immunology La Jolla, California, United States
Introduction/Rationale: We recently reported that ICOS, OX40, and CD30 are essential for the long-term maintenance of Th2-biased allergen-reactive lung tissue-resident memory CD4 T (Trm) cells. However, their role in sustaining Th1/Th17 Trm cells remains unclear.
Methods: To address this, mice were exposed intranasally to a combination of house dust mite (HDM), cyclic di-GMP (c-di-GMP), and lipopolysaccharide (LPS), resulting in a biased Th1/Th17 response with ~6-fold increase in neutrophil accumulation compared with HDM alone.
Results: Therapeutic co-administration of blocking antibodies to ICOSL, OX40L, and CD30L during tertiary allergen exposure reduced the accumulation of CD44hiCD62Llo CD4+ lung Trm cells by ~70%, although this reduction was weaker than that observed in Th2 asthmatic mice. Analysis of mouse scRNA-seq data revealed prominent expression of receptors for TL1A (DR3) and GITRL (GITR) in Th1 and Th17 cells, while ICOS expression was maintained across these cells similar to Th2 cells, in line with transcriptomic analyses of allergen-reactive human CD4 Trm cells. Correspondingly, short-term therapeutic blockade of ICOSL together with TL1A and GITRL reduced lung Trm accumulation by ~90%. Moreover, dual blockade of TL1A with GITRL was also effective, reducing the long-lasting CD4 Trm population in the lungs by ~80%.
Conclusion: Collectively, our data highlight cooperative costimulatory pathways in determining the persistence of CD4 Trm cells and identify TL1A and GITRL as promising therapeutic targets to achieve long-term tolerance in patients with Th1 and Th17-biased tissue inflammation.
