The principle of central tolerance implies that developing T cells be exposed to tissue antigens and become deleted if they display auto-reactivity features. However, the understanding of gene expression control has engendered the problem of how peripheral tissue-specific antigens reach the anatomic organ where the central tolerance process takes place – the thymus. Among mechanisms that provide explanation for this problem are those that either circumvent the gene expression aspect (passive diffusion of antigens through the blood) or embrace it (promiscuous intrathymic gene expression). There are also data that indicate the tolerogenic role for dendritic cells residing in thymic compartments. These dendritic cells have been suggested to be able to collect peripheral antigens in tissues and supply them to the thymus. In this line I have found very interesting publication that describes plasmacytoid dendritic cells as potential players in the central tolerance induction.
Authors show that CCR9-deficient mice have decreased numbers of thymic plasmacytoid dendritic cells. Following this initial finding it is concluded that WT pDCs possess the advantage over CCR9-deficient pDCs in homing ability to the thymus and additionally to the lamina propria and the intestinal intraepithelium. To prove such point investigators have used diverse techniques that included parabiosis experiments (animals of different genetic background that are surgically joined to enable blood cells exchange), generation of bone marrow chimaeras combined with adoptive transfer methodology and in vivo enrichment of dendritic cell populations by grafting mice with tumors that express Flt3L.
To address the possible role of plasmacytoid dendritic cells in the central tolerance authors examine if pDCs may be able to transport OVA antigen to the thymus in order to induce the deletion of OVA-specific CD4 T cells there. Following the generation of bone marrow chimaeras that enable monitoring fate of transgenic OT-II thymocytes and the intravenous injection of pDCs loaded with OVA antigen it is demonstrated that this is indeed the case. However, the tolerogenic activity of pDCs is abrogated when these cells become activated with TLR9 ligand. For the full ability to delete CD4 T cells pDCs need to express CCR9 – as this molecule directs them to the thymus but is not involved in the proper deletion mechanism. The publication also contains clever visualization scheme devised to prove that pDCs are actually capable to collect tissue antigens and shuttle them to the thymus.
So, it seems like plasmacytoid dendritic cells beyond their known participation in viral defense and peripheral Treg induction may have an additional function. The deletion data obtained with OVA transgenic system is very convincing and entice to seek some further evidences supporting this novel physiological role of pDCs. For example, it might be interesting to look for a link between the ability of pDCs to transport peripheral antigens to the thymus and tolerance to intestinal commensal flora. It is well established that postpartum bacterial colonization has profound effects on the functionality of immune system. May it also influence the central tolerance process? I don’t know the answer, but I think there are tools like gnotobiotic mono-colonized mice and TCR transgenic systems that may enable us to get some more information.
Hadeiba H, Lahl K, Edalati A, Oderup C, Habtezion A, Pachynski R, Nguyen L, Ghodsi A, Adler S, & Butcher EC (2012). Plasmacytoid dendritic cells transport peripheral antigens to the thymus to promote central tolerance. Immunity, 36 (3), 438-50 PMID: 22444632