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C.M. Watte, J.E. Stein–Streilein; Unique Homing Characteristics for Tolerogenic APC in ACAID . Invest. Ophthalmol. Vis. Sci. 2005;46(13):1042.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: It is known that the chemokine receptor profile on APC determine their migratory pathway. The purpose of this study was to determine the chemokine receptors that direct the migration of eye–derived APC to the marginal zone (MZ) of the spleen instead of the T cell areas during the generation of ACAID–induced peripheral tolerance. The role of MZ stromal cells, MZ metalophilic macrophages, in the induction of ACAID was considered. Materials and Methods: The following two types of ACAID–inducing APC were studied: TGFß treated, antigen pulsed, bone marrow (BM) derived APC and macrophage hybridoma cell, # 59. ACAID–inducing BM–APC, LPS treated APC and antigen pulsed APC were evaluated by RT–PCR using specific primers for CCR6, CCR7 and CXCR4. The in vivo homing characteristics of ACAID–inducing APC were studied immunohistochemically in frozen spleen sections after a.c. inoculation. The MZ was identified with mAb to sialoadhesin on MZ metallophils, 3D6, and the migrating APC by mAB F4/80. The role of the metallophils in ACAID mice was studied in osteopetrosis (Csf1op/Csf1op) mice (and their WT littermates), a mutant mouse strain that lacks MZ metalophills. Results: In vitro generated ACAID–inducing APC downregulated CCR6 mRNA expression and upregulated CXCR4 expression but failed to increase CCR7 mRNA . Immunohistochemical analyses of frozen spleen tissue showed that i.v. inoculated ACAID–inducing APC migrated to the MZ of the spleen. In contrast to littermate controls, osteopetrosis mice failed to develop efferent Treg cells and suppression of DTH following a.c. inoculation of antigen. Conclusions: ACAID–inducing APC express a unique chemokine receptor profile that correlates with their migration to the MZ and not the T cell areas of the spleen. The profile is consistent with our previous observations that ACAID inducing APC interact with MZ B, T and iNKT cells in the MZ following a.c. inoculation of antigen. This is the first report to show that MZ metallophils are required for ACAID induction and confirms that the MZ is the area of the spleen where cellular interactions take place.
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