Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

Hadeiba, Husein; Lahl, Katharina; Edalati, Abdolhossein; Oderup, Cecilia; Habtezion, Aida; Pachynski, Russell K.; Nguyen, Linh P.; Ghodsi, Asma; Adler, Sarah; Butcher, Eugene C.

doi:10.1016/j.immuni.2012.01.017

Cited by 224 publications

(258 citation statements)

References 35 publications

Supporting

Mentioning

235

Contrasting

Unclassified

Order By: Relevance

“…Thymic DCs and mTECs have a half-life of about 2-3 weeks and at least for mTECs, considerable differences in tissue-restricted antigen expression between different cells have been described 44 . Our and other data support the idea that thymic DCs sample the blood stream for proteins, and peripheral DCs can take up antigens, migrate to the thymus and delete the corresponding T cells 8,12 . Changes in the periphery would therefore be expected to impact on the peptides presented in the thymus.…”

Section: Discussionsupporting

confidence: 87%

“…Although, in contrast to mTECs, they are not specialized in expressing tissue-specific antigens such as proinsulin, they can efficiently capture these from mTECs and present them to developing T cells, inducing their deletion, a process that involves autoimmune regulator expression (AIRE) in mTECs 6,7 . A role of plasmacytoid DCs (pDCs) in negative selection has only been described very recently 8 and thymic B cells might also be able to contribute to negative selection 9 . Although so far there is no direct proof that the different subsets of thymic APCs present different sets of peptides, there are two strong lines of indirect evidence supporting this notion.…”

mentioning

confidence: 99%

“…In addition to constitutively expressed house-keeping proteins and cell-type-specific proteins, mTECs express tissue-restricted antigens such as insulin under the control of the AIRE transcription factor 10,11 . Also, blood-born mDCs and pDCs can import peripheral antigens into the thymus where they delete self-reactive thymocytes 8,12 . Second, both the MHC I and II antigenprocessing machinery differs between different thymic APCs, which should influence the epitopes that are generated [13][14][15][16] .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Exploring the MHC-peptide matrix of central tolerance in the human thymus

et al. 2013

View full text Add to dashboard Cite

Ever since it was discovered that central tolerance to self is imposed on developing T cells in the thymus through their interaction with self-peptide major histocompatibility complexes on thymic antigen-presenting cells, immunologists have speculated about the nature of these peptides, particularly in humans. Here, to shed light on the so-far unknown human thymic peptide repertoire, we analyse peptides eluted from isolated thymic dendritic cells, dendritic cell-depleted antigen-presenting cells and whole thymus. Bioinformatic analysis of the 842 identified natural major histocompatibility complex I and II ligands reveals significant crosstalk between major histocompatibility complex-class I and II pathways and differences in source protein representation between individuals as well as different antigen-presenting cells. Furthermore, several autoimmune-and tumour-related peptides, from enolase and vimentin for example, are presented in the healthy thymus. 302 peptides are directly derived from negatively selecting dendritic cells, thus providing the first global view of the peptide matrix in the human thymus that imposes self-tolerance in vivo.

show abstract

Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Exploring the MHC-peptide matrix of central tolerance in the human thymus

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23)(24)(25) and humans (26)(27)(28)(29)(30). Surface expression of CD2 divides human pDCs into two distinct subsets.…”

mentioning

confidence: 99%

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Zhang

Gregorio

Iwahori³

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Plasmacytoid dendritic cells (pDCs) are known mainly for their secretion of type I IFN upon viral encounter. We describe a CD2 hi CD5 + CD81 + pDC subset, distinguished by prominent dendrites and a mature phenotype, in human blood, bone marrow, and tonsil, which can be generated from CD34 + progenitors. These CD2 hi CD5 + CD81 + cells express classical pDC markers, as well as the toll-like receptors that enable conventional pDCs to respond to viral infection. However, their gene expression profile is distinct, and they produce little or no type I IFN upon stimulation with CpG oligonucleotides, likely due to their diminished expression of IFN regulatory factor 7. A similar population of CD5 + CD81 + pDCs is present in mice and also does not produce type I IFN after CpG stimulation. In contrast to conventional CD5 − CD81 − pDCs, human CD5 + CD81 + pDCs are potent stimulators of B-cell activation and antibody production and strong inducers of T-cell proliferation and Treg formation. These findings reveal the presence of a discrete pDC population that does not produce type I IFN and yet mediates important immune functions previously attributed to all pDCs.P lasmacytoid dendritic cells (pDCs) are a distinct lineage of bone-marrow-derived cells that reside mainly in blood and lymphoid organs in the steady state, but can also be found in sites of infection, inflammation, and cancer (1). As one of the two principal lineages of dendritic cells, pDCs diverge from conventional DCs (cDCs) during maturation in the bone marrow and are recognized mainly for their rapid and massive production of type I IFN (IFNα/β) in response to viral infection (2). Although generally viewed as weak antigen-presenting cells by comparison with cDCs, pDCs interact with many types of cells, such as NK cells, cDCs, T cells, and B cells through their secretion of cytokines and chemokines in addition to type I IFN, as well as through their expression of various costimulatory molecules (3, 4). Thus, pDCs are capable of activating CD4 + helper and regulatory T cells and CD8 + cytotoxic T cells (5-16). They can also stimulate B-cell activation, differentiation into plasma cells, and antibody production through mechanisms that are not yet completely understood (17)(18)(19)(20)(21)(22).Whether the diverse functions of pDCs are mediated by the same cells responding to different environmental cues or by distinct preprogrammed subsets or lineages is not clear, although several reports suggest the existence of phenotypically distinct subpopulations of pDCs in mice (23-25) and humans (26-30). Surface expression of CD2 divides human pDCs into two distinct subsets. Whereas both CD2 lo and CD2 hi pDCs produce type I IFN, the CD2 hi subset secretes more IL12p40, triggers more T-cell proliferation (26), and is relatively resistant to apoptosis on the basis of higher BCL2 expression (28). Here we show that CD2 hi pDCs contain a unique subpopulation that expresses CD5 and CD81. Unlike CD2 hi CD5 − CD81 − pDCs, CD2 hi CD5 + CD81 + pDCs fail to produce type 1 IFN but ...

show abstract

“…In the present study, 100% of aged mice became tolerant to allogeneic skin grafts, suggesting that tolerance induction in our model is not hindered by thymic atrophy and/or compensated by peripheral mechanisms. Our thymectomy data suggest that Tregs are being produced in response to donor antigens in peripheral tissues, rather than when antigen sampled in the periphery is recirculated to the thymus (43). Facilitating cells in WBM have been shown to induce antigen-specific Tregs that enhance progenitor cell engraftment (44), but this is unlikely to be the sole mechanism in the current model, as Tregs and allogeneic tolerance were also generated when mice were transplanted with purified LSK progenitor cells lacking the facilitating cell population.…”

Section: Discussionmentioning

confidence: 88%

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

Morison

Homann

Hammett

et al. 2014

American Journal of Transplantation

View full text Add to dashboard Cite

y Co-senior authors.Mixed hematopoietic chimerism is a powerful means of generating donor-specific tolerance, allowing longterm graft acceptance without lifelong dependence on immunosuppressive drugs. To avoid the need for whole body irradiation and associated side effects, we utilized a radiation-free minimal conditioning regime to induce long-term tolerance across major histocompatibility barriers. We found that low-dose busulfan, in combination with host T cell depletion and short-term sirolimus-based immunosuppression, facilitated efficient donor engraftment. Tolerance was achieved when mice were transplanted with whole or T cell-depleted bone marrow, or purified progenitor cells. Tolerance induction was associated with an expansion in regulatory T cells and was not abrogated in the absence of a thymus, suggesting a dominant or compensatory peripheral mode of tolerance. Importantly, we were able to generate durable chimerism and tolerance to donor skin grafts in both young and aged mice, despite age-related thymic atrophy and immune senescence. Clinically, this is especially relevant as the majority of transplant recipients are older patients whose immune recovery might be dangerously slow and would benefit from radiation-free minimal conditioning regimes that allow efficient donor engraftment without fully ablating the recipient immune system.

show abstract

Plasmacytoid Dendritic Cells Transport Peripheral Antigens to the Thymus to Promote Central Tolerance

Cited by 224 publications

References 35 publications

Exploring the MHC-peptide matrix of central tolerance in the human thymus

Exploring the MHC-peptide matrix of central tolerance in the human thymus

A distinct subset of plasmacytoid dendritic cells induces activation and differentiation of B and T lymphocytes

Establishment of Transplantation Tolerance via Minimal Conditioning in Aged Recipients

Contact Info

Product

Resources

About