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Regulatory dendritic cell expression of MHC II and IL ‐10 are jointly requisite for induction of tolerance in a murine model of OVA ‐asthma
Author(s) -
Huang H.,
Dawicki W.,
Lu M.,
Nayyar A.,
Zhang X.,
Gordon J. R.
Publication year - 2013
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12203
Subject(s) - foxp3 , immunology , dendritic cell , immune tolerance , cd86 , t cell , chemokine , interleukin 4 , biology , medicine , immune system
Background Allergen‐presenting dendritic cells differentiated with IL ‐10 ( DC 10) reverse the asthma phenotype in mice by converting their Th2 cells to regulatory T cells ( T regs). DC 10 express elevated levels of IL ‐10, but substantially reduced levels of MHCII and costimulatory molecules, so the relationships between these factors with each other and tolerogenicity have not been clearly elucidated. Methods We assessed the roles of these inputs in DC 10 reversal of OVA ‐associated asthma‐like disease by treating affected mice with OVA ‐pulsed DC 10 generated from wild‐type or IL ‐10‐sufficient MHCII −/− or CD 80/ CD 86 −/− mice, or with MHCII ‐intact IL ‐10‐silenced DC 10. Results IL ‐10 silencing did not discernibly affect the cells' immunobiology (e.g., costimulatory molecules, chemokines), but it eliminated IL ‐10 secretion and the cell's abilities to induce tolerance, as determined by assessments of airway hyper‐responsiveness, eosinophilia, and T h2 responses to recall OVA challenge. MHCII −/− DC 10 expressed normal levels of IL ‐10, but, nevertheless, were unable to induce allergen tolerance in asthma phenotype mice, while tolerance induced by CD 80/ CD 86 −/− DC 10 was attenuated but not eliminated. We also assessed the induction of multiple T reg cell markers (e.g., ICOS , PD ‐1, GITR ) on pulmonary CD 25 + Foxp3 + cells in the treated mice. Wild‐type DC 10 treatments upregulated expression of each marker, while neither IL ‐10‐silenced nor MHCII −/− DC 10 did so, and the CD 80/86 −/− DC 10 induced an intermediate T reg cell activation phenotype. Conclusion Both IL ‐10 and MCHII expression by DC 10 are requisite, but not sufficient for tolerance induction, suggesting that DC 10 and Th2 effector T cells must be brought together in a cognate fashion in order for their IL ‐10 to induce tolerance.