Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts

Abstract

The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. Here we identify plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes. In the lymph node, alloantigen-presenting pDCs induced the generation of CCR4+ CD4+ CD25+ Foxp3+ regulatory T cells (Treg cells). Depletion of pDCs or prevention of pDC lymph node homing inhibited peripheral Treg cell development and tolerance induction, whereas adoptive transfer of tolerized pDCs induced Treg cell development and prolonged graft survival. Thus, alloantigen-presenting pDCs home to the lymph nodes in tolerogenic conditions, where they mediate alloantigen-specific Treg cell development and allograft tolerance.

On watching the watchers: IDO and type I/II IFN

“…Whatever the mechanisms involved in the control of IFN-a by IDO, which is in turn controlled by the former, the present observations by Manlapat et al [20], combined with the previous data on the role of pDC and IFN in the balance of inflammation and tolerance [4,5,9,10,21], call attention to the importance of the IDO-dependent effects of B7 ligands, including CTLA-4-Ig [11], as therapeutic agents. At the same time, these studies further establish IDO as a truly immunoregulatory enzyme.…”

“…pDC, nonetheless, participate in down-regulating exacerbated immune responses and in establishing tolerance [9]. Maturing pDC have an intrinsic ability to inhibit immune responses by inducing IL-10-producing T regulatory (Treg) cells.…”

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

“…36 Given our current observations that nonfunctional CD8 ϩ T cells, ie, failure to lyse or produce interferon-␥ when stimulated with minor H alloantigen, can also be expanded from some of our donors (&2, &3, and (2, data not shown), we speculate that naturally established tolerance to minor H antigens may be the result of either the presence of minor H antigen-specific T REG and/or the induction of T-cell anergy. Several experimental transplantation models have demonstrated that the establishment and maintenance of stable allograft tolerance depend on systemically persisting alloantigen-expressing microchimeric cell types, such as lymphocytes, 37,38 DCs, [39][40][41][42] or both. 17 These cell types continuously present alloantigen to host T cells under noninflammatory conditions, which may lead to active deletion of host alloreactive T cells 37 and/or the induction of alloreactive adaptive T REG .…”

Staphylococcus aureus-Derived Staphopain B, a Potent Cysteine Protease Activator of Plasma Chemerin

“…Although a comprehensive analysis of pDC function remains incomplete, current data suggest that pDC may occupy a central stage as regulators of immune responses, able to modulate the functions of cells involved in both innate and acquired immunity, including NK, myeloid dendritic cells as well as T and B cells (35). Moreover, immature pDC can differentiate either into proinflammatory APC, capable for example of producing large amounts of type I IFNs in response to viral and microbial stimuli (36), or into potent inducers of T regulatory cells, thus suppressing local immune responses (37)(38)(39). Immature pDC circulate normally in blood and lymphoid organs, and are recruited to peripheral tissues during inflammation.…”