Transient Therapeutic Inhibition of Multiple Costimulatory Molecules Modulates Persistence of

Lung Tissue-resident Memory T cells

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B637
Abstract ID: 7488

Presenting Author:
Gurupreet Singh Sethi , Instructor at La Jolla Inst. for Immunol.

Abstract:

Costimulatory molecules, crucial for priming of T cells, development of T cell memory, and establishment of inflammatory diseases, have an unknown role in prolonged survival of Tissue-resident memory T (Trm) cells and the maintenance of relapsing inflammation. Single-cell RNA-seq data from asthmatic lungs revealed high expression of OX40, CD30L, and ICOS on CD4 T cells, aligning with transcriptomic analysis of allergen-reactive mouse CD4 Trm cells in a relapsing asthma model. Accordingly, the transient blockade of ICOSL alone or CD30L and OX40L together during tertiary allergen inhalation effectively reduced the expansion of CD44^hiCD62L^loCD4⁺ lung Trm by 40-50%, further reducing to 80-90% when concurrently targeting all three molecules and corresponding to dramatically decreased lung inflammation. Administering FTY720 with the blocking antibodies highlighted costimulatory molecules govern reactivation of both lung Trm and circulatory memory T cells that contribute to the maintenance of Trm pool. Costimulation blockade limited Trm proliferation and their continued responsiveness upon future allergen insults, explaining improved lung function. Dual blockade of ICOSL with OX40L, or ICOSL with CD30L, reproduced the effects of blocking all molecules together in limiting persistence of high numbers of functional Trm, suggesting that targeting ICOS signaling along with CD30 or OX40 signaling holds promise as a clinical treatment for various immune-mediated inflammatory diseases