During ACAID induction, MIP-2-producing F4/80+ APCs appear first in the bloodstream and then in the spleen. MIP-2 is a murine functional analogue of human IL-8. In ACAID, the MIP-2 chemokine is critical to the recruitment of NKT cells and facilitating tolerance induction and was absolutely required for generation of the Ag specific CD8+ Treg cells (23). ACAID also did not occur in mice that were deficient in CXCR2, the high affinity receptor for MIP-2. Thus, when the ACAID-inducing signal, F4/80+ APC, leaves the eye, it begins the path toward tolerance induction by recruiting the types of cells that are needed to induce differentiation of T regulatory cells.
Another difference between immunogenic APC and tolerogenic APC is the chemokine receptor profile. Microgene array analyses performed in our laboratory showed that bone marrow derived F4/80+ APC generated in cultures of bone marrow cells with L929 media expressed a unique chemokine receptor profile. BM-derived F4/80+ APC treated with TGF^2 and antigen were capable of inducing antigen specific tolerance in both naive and previously sensitized mice (43-45). The in vitro generated tolerogenic BM-derived APCs do not express the critical chemokine receptor (CCR7) that is needed for cells to traffic to the T-cell areas of the spleen (43). This observation supports the postulate that the induction of tolerance occurs in the MZ rather than the T-cell areas of the spleen.
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