Enhanced Induction of Regulatory Macrophages Upon Azathioprine/Infliximab Combination Treatment In Vitro

Abstract

G A A b st ra ct s to determine whether Treg defects resulted from either increased apoptosis or decreased maintenance of Foxp3 expression in Tregs. Methods/Results: WASP-deficient DCs led to decreased In Vitro generation of adaptive Tregs. More importantly, upon transfer of Foxp3cells into recipient mice, there was a marked reduction in the generation of Foxp3+ inducible Tregs in WASP/RAG DKO mice compared to RAG KO controls. The defects in WT Treg function in chimeric mice could not be explained by alterations in the maintenance or apoptosis of Foxp3+ donor cells in WASP/RAG DKO mice compared to RAG KO mice. Employing an In Vitro suppression assay, WT Tregs functioned normally when MLN DCs isolated from either WT or WASP-deficient mice were used as APCs. In contrast, there was aberrant Treg function when DCs were isolated from WASP/RAG DKO mice. Conclusions: WASP deficiency in innate immune cells leads to defective Treg generation and function In Vivo. Similarly, there was reduced generation of WT Tregs In Vitro in the presence of WASPdeficient DCs. However, Treg function was compromised only when DCs were harvested from WASP/RAG DKO mice but not WASP-deficient mice, suggesting an intrinsic aberrancy in WASP-deficient DCs unmasked in a lymphopenic setting. In summary, colitis in chimeric mice may result from DC-driven alterations in Treg number and function.