Apoptotic cells (ACs) promote immunologic tolerance but the early innate mechanism(s) involved in the process are not known. Here we report that administration of ACs i/v induced rapid splenic expression of the regulatory T cell chemokine CCL22 by CD169+ marginal zone macrophages (MZMs). Similarly, in-vitro culture with ACs lead to expression of CCL22 in purified MZMs, but not CD11c+ dendritic cells (DCs) and conditioned media from MZM cocultures induced migration of Tregs in a CCL22 dependent manner. Administration of a soluble antagonist for the CCL22 receptor (i.e. CCR4) skewed the early innate immune response to ACs in-vivo shifting the balance from regulatory (IL-10, TGF-β) to inflammatory (TNF-α, IL-6, IL-12) cytokine production in splenic DCs and macrophages. Similarly, CCR4 blockade inhibited splenic accumulation of Tregs after apoptotic cell injection i/v and enhanced effector T cell responses to AC-associated antigens. Short-term CCR4 inhibition at the time of i/v apoptotic cell challenge (i.e. blockade only at the time of apoptotic cell administration) reversed AC-mediated tolerance to skin allografts in both primary recipients and in Treg adoptive transfers to secondary recipients instead promoting more rapid rejection. Suggesting a primary role for CCL22 in AC tolerance. Thus, we show for the first time that selective induction of CCL22 by MZMs is an essential early innate step in the generation of infectious immune tolerance to apoptotic self.
- Copyright © 2013 by The American Association of Immunologists, Inc.