Human Peripheral Lymphoid Tissues Contain Autoimmune Regulator-Expressing Dendritic Cells

• DOI: 10.2353/ajpath.2010.090956
• Publication Date: 2010-01-22T02:49:41Z
• Authors: Pietro Luigi Poliani; Kai Kisand; Veronica Marrella; Maria Ravanini; Luigi Daniele Not...; Anna Villa; Pärt Peterson; Fabio Facchetti
• Keywords: Adult; Male; 0301 basic medicine; Adolescent; Lymphoid Tissue; AIRE Protein; Dendritic Cells; Middle Aged; peripheral tolerance; Immunohistochemistry; Human peripheral lymphoid tissues; 3. Good health; 03 medical and health sciences; Fetus; Phenotype; Organ Specificity; Immune Tolerance; Human peripheral lymphoid tissues; Autoimmune Regulator (AIRE); dendritic cells; peripheral tolerance; Autoimmune Regulator (AIRE); Humans; Female; dendritic cells; Antigens; Transcription Factors

Autoimmune regulator (AIRE) modulates the expression of tissue-restricted antigens (TSAs) and promotes central tolerance in the thymus. However, few autoreactive T cells escape negative selection and reach the periphery, where peripheral tolerance is required to avoid autoimmunity. Murine lymph nodes (LNs) have been shown to contain "stromal" cells expressing AIRE and TSAs. Here we report the occurrence of AIRE-expressing cells in human peripheral lymphoid tissues, including LNs, tonsils, and gut-associated lymphoid tissue, with the exception of the spleen. Notably, AIRE+ cells are absent in fetal LNs and, in postnatal life, they are more numerous in abdominal than in superficial LNs, thus suggesting that their development in periphery may depend on instructive signals from microenvironment and antigen challenge. Extrathymic AIRE+ cells show a dendritic morphology, consistently express human leukocyte antigen-DR (HLADR) and fascin, and are largely positive for CD11c and S100 and for the dendritic cell-activation markers CD40, CD83, DC-LAMP/CD208, and CCR7. Lymphoid, myelomonocytic, mesenchymal, and epithelial cell lineage markers are negative. The HLADRhigh/AIRE+ cell fraction isolated from mesenteric LNs expressed TSAs (insulin, CYP17A1, and CYP21A2), as well as molecules associated with tolerogenic functions, such as interleukin-10 and indoleamine 2,3-dioxygenase. Data indicate that AIRE+ cells in human peripheral lymphoid tissues correspond to a subset of activated interdigitating dendritic cells expressing TSAs and the tolerogenic molecules indoleamine 2,3-dioxygenase and interleukin-10, suggestive of a potential tolerogenic function.