Dexamethasone promotes tolerance in vivo by enriching CD11cloCD40lo tolerogenic macrophages

We previously showed that antigen immunization in the presence of the immunosuppressant dexamethasone (a strategy we termed “suppressed immunization”) could tolerize established recall responses of T cells. However, the mechanism by which dexamethasone acts as a tolerogenic adjuvant has remained unclear. In the present study, we show that dexamethasone enriches CD11cloCD40lo macrophages in a dose-dependent manner in the spleen and peripheral lymph nodes of mice by depleting all other CD11c+CD40+ cells including dendritic cells. The enriched macrophages display a distinct MHC class II (MHC II)loCD86hi phenotype. Upon activation by antigen in vivo, CD11cloCD40lo macrophages upregulate IL-10, a classic marker for tolerogenic antigen-presenting cells, and elicit a serum IL-10 response. When presenting antigen in vivo, these cells do not elicit recall responses from memory T cells, but rather stimulate the expansion of antigen-specific regulatory T cells. Moreover, the depletion of CD11cloCD40lo macrophages during suppressed immunization diminishes the tolerogenic efficacy of the treatment. These results indicate that dexamethasone acts as a tolerogenic adjuvant partly by enriching the CD11cloCD40lo tolerogenic macrophages.