Allergen-specific regulatory T cells form lung resident memory capable of suppressing Th2 recall responses to allergen

Introduction/Rationale: Intranasal house dust mite (HDM) exposure elicits allergen-peptide (p):MHCII-specific Th2 and Tregs in the airways of mice. The balance between opposing pro- and anti-inflammatory functions of these cell populations may influence the outcome of airway re-exposure to HDM. However, the number of cells specific for known HDM derived epitopes in B6 mice is low, making longitudinal studies of these cell populations difficult.

Methods: To overcome this obstacle, we developed an approach using adoptive transfer of a physiologically relevant number of CD4+ T cells from a fixed TCR beta chain transgenic (1-DERβ) mouse and corresponding HDM p:MHCII tetramer to simultaneously interrogate the trafficking, memory formation, and functional properties of HDM-specific Th2 and Treg cells.

Results: Naïve 1-DERβ CD4+ T cells generated similar frequencies of Th2 and Treg fates as endogenous HDM-specific cells. Parabiosis experiments demonstrated HDM-specific Tregs form stable tissue-resident memory (Trm) cells in the lungs, similar to their previously described Th2 counterparts. Single cell RNA sequencing of these cell populations revealed shared expression of Trm genes, including the chemokine receptors CXCR6 and CCR8. Co-adoptive transfer of wild type and chemokine receptor deficient 1-DERβ cells revealed differential roles for CXCR6 and CCR8 in the generation and maintenance in the lung. Depletion of Tregs in the memory phase led to increased Th2 responses in the lung upon allergen rechallenge.

Conclusion: Thus, our findings are consistent with a model where lung-resident allergen-specific Tregs persist long term and are capable of suppressing resident Th2 cells following allergen rechallenge.