Type 2 conventional dendritic cells and regulatory T cells form a barrier tissue circuit to control allergic inflammation

Summary Chronic allergic diseases are driven by T helper type 2 (Th2) cells in barrier tissues. Despite their profound effects on tissue physiology, Th2 cells represent a rare cell population within tissues, suggesting mechanisms restraining Th2 cell expansion at barrier sites that remain ill defined. Using a murine model of allergic asthma, we demonstrate that effector Th2 cells promote cDC2 activation within the lungs, including expression of the CCR4 ligands that attract Foxp3+ regulatory T cells (Tregs). Selective deletion of Ccr4 in Tregs during the effector Th2 cell response led to increased lung Th2 cells, activated cDC2s, and allergic inflammation. Mechanistically, CCR4 promoted Treg trafficking efficiency and was required to specifically control tissue cDC2 co-stimulatory molecule expression. Lastly, in the airways of humans with allergy, the expression of the CCR4 ligands in activated cDCs correlated with Treg enrichment. In sum, we define a cDC2-Treg feedback circuit within a barrier tissue that restrains effector Th2 cell expansion, revealing a novel role for tissue cDC2s in controlling Th2 cell biology. Competing Interest Statement RAR participated in a Regeneron pharmaceuticals-sponsored study and has been a consultant for Sanofi. ACV has been a consultant to Bristol Myers Squibb and Merck; ACV has financial interest in 10X Genomics. 10X Genomics designs and manufactures gene sequencing technology for use in research, and such technology is being used in this research; these interests were reviewed by The Massachusetts General Hospital and Mass General Brigham in accordance with their institutional policies. Footnotes Funding statement: This work was supported by the National Institutes of Health, National Institute of Heart, Lung, and Blood (R03 HL164370 to RAR); National Institute of Allergy and Infectious Diseases (R21 AI173732 to RAR); National Institute of Health Director’s New Innovator Award (DP2CA247831 to ACV), an American Lung Association Innovation Award (to RAR); Massachusetts General Hospital Transformative Scholar in Medicine Award (to RAR); Harvard Catalyst award (UM1TR004408 to VB, WJG, and SHS). Disclosure statement: RAR participated in a Regeneron pharmaceuticals-sponsored study and has been a consultant for Sanofi. ACV has been a consultant to Bristol Myers Squibb and Merck; ACV has financial interest in 10X Genomics. 10X Genomics designs and manufactures gene sequencing technology for use in research, and such technology is being used in this research; these interests were reviewed by The Massachusetts General Hospital and Mass General Brigham in accordance with their institutional policies.