Summary 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 in the spleen and peripheral lymph nodes, dexamethasone dose-dependently enriches CD11cloCD40lo macrophages by depleting all other CD11c+CD40+ cells including dendritic cells. The enriched macrophages display a distinct MHC IIloCD86hi phenotype. Upon activation by a recall antigen in vivo, they upregulate IL-10, a classic marker for tolerogenic antigen-presenting cells, and elicit a serum IL-10 response. When presenting a recall antigen in vivo, they do not elicit recall responses of memory T cells, but rather stimulate the expansion of antigen-specific regulatory T cells. Moreover, depletion of CD11cloCD40lo macrophages during suppressed immunization diminishes the latter’s tolerogenic efficacy. These results indicate that dexamethasone acts as a tolerogenic adjuvant partly by enriching the CD11cloCD40lo tolerogenic macrophages.
We previously showed that the immunosuppressant dexamethasone (DEX), when used as a “tolerogenic adjuvant” during antigenic immunization, preferentially expands Ag-specific CD4+CD25+Foxp3+ regulatory T cells (Treg) and forcefully steers the immunization toward Ag-specific tolerance. However, the mechanisms underlying the tolerogenic efficacy of DEX remain undetermined. In this study, we show that while dose-dependently depleting dendritic cells in the spleen and lymph nodes, DEX selectively retains and modifies in the spleen a macrophage subset expressing low levels of CD11c (designated “DEX-MΦs”). DEX-MΦs constitutively express CD86 and, yet, down-regulate MHC II. Upon recall-Ag stimulation, DEX-MΦs upregulate IL-10, a classic marker for tolerogenic APCs. When presenting recall Ag in vivo, DEX-MΦs do not elicit responses of effector T cells, but rather stimulate the expansion of Ag-specific Treg. Thus, we suggest that DEX may exert its adjuvant efficacy partly by selectively retaining tolerogenic DEX-MΦs and using them as the alternate APCs.
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