A Novel Pathway of Antigen Presentation by Dendritic and Endothelial Cells: Implications for Allorecognition and Infectious Diseases

Smyth, Lesley A.; Herrera, Osquel Barroso; Golshayan, Déla; Lombardi, Giovanna; Lechler, Robert I.

doi:10.1097/01.tp.0000231347.06149.ca

Cited by 75 publications

(51 citation statements)

References 38 publications

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“…38,39 Exosomes can also be the vehicle for transferring transmembrane proteins, and the relocated MHC can endow the recipient APC with the ability to prime T cells. 41,43,[45][46][47] Most relevant to our studies, the transfer of transmembrane proteins can be potentiated with prior freeze/thaw killing of the donor cells. 42 In our studies, irradiation and cell death, physiologic in the context of alloSCT, were key as we did not see hybrid DCs in stable mixed BM chimeras (not shown), and the microscopy images suggest transfer of relatively large membrane fragments.…”

Section: Discussionmentioning

confidence: 99%

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Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation

Wang¹,

Matte-Martone

et al. 2011

Blood

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Recipient antigen-presenting cells (APCs) initiate GVHD by directly presenting host minor histocompatibility antigens (miHAs) to donor CD8 cells. However, later after transplantation, host APCs are replaced by donor APCs, and if pathogenic CD8 cells continue to require APC stimulation, then donor APCs must cross-present host miHAs. Consistent with this, CD8-mediated GVHD is reduced when donor APCs are MHC class I ؊ . To study cross-presentation, we used hosts that express defined MHC class I K b -restricted miHAs, crossed to K b -deficient backgrounds, such that these antigens cannot be directly presented. Cross-priming was surprisingly efficient, whether antigen was restricted to the hematopoietic or nonhematopoietic compartments. Cross-primed CD8 cells were cytolytic and produced IFN-␥. CD8 cells were exclusively primed by donor CD11c ؉ cells, and optimal cross-priming required that they are stimulated by both type I IFNs and CD40L. In studying which donor APCs acquire host miHAs, we made the surprising discovery that there was a large-scale trans- IntroductionAllogeneic hematopoietic stem cell transplantation (alloSCT) can be a life-saving therapy for hematologic malignancies and acquired or inherited nonmalignant disorders of blood cells. Mature donor T cells in allografts play important roles in alloSCT. They contribute to T-cell reconstitution in the recipient, promote donor hematopoietic engraftment, and mediate an anti-tumor effect called GVL. Unfortunately, donor T cells can broadly target host tissues causing GVHD. 1 Because of GVHD, all patients receive some type of prophylactic immunosuppression, either by depleting T cells from the allograft, or more commonly, with pharmacologic agents and that inhibit T-cell function. However, even with pharmacologic immunosuppression, GVHD remains a major cause of morbidity and mortality. Novel approaches are clearly needed.GVHD is initiated by antigen-presenting cells (APCs) that prime alloreactive donor T cells. 1 In MHC-matched alloSCT, donor T cells target minor histocompatibility antigens (miHAs), which are the peptide products of polymorphic genes that distinguish the host from the donor. We previously found that direct presentation of MHC class I-restricted miHAs by recipient APCs is necessary for CD8-mediated GVHD in an MHC-matched, multiple miHAmismatched model. 2 However, although host APCs are key players, there was reason to believe that donor APCs should also play a significant role, as GVHD can begin and persist at times after transplantation when host hematopoietic cells, including APCs, are largely if not completely replaced by donor-derived cells. If, at these later times, alloreactive CD8 cells still need to be primed by professional APCs to be pathogenic, one would predict that donor APCs crosspresenting host miHAs would be important. On the other hand, it is possible that GVHD is maintained by a small number of persistent host APCs. 3 In studies to address the role of donor APCs, we previously reported that CD8-mediated GVHD against miHAs is r...

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Section: Discussionmentioning

confidence: 99%

“…[38][39][40][41][42][43][44][45][46] T cells in contact with targets can acquire target cell-derived MHC in a contact-dependent manner. 38,39 Exosomes can also be the vehicle for transferring transmembrane proteins, and the relocated MHC can endow the recipient APC with the ability to prime T cells.…”

mentioning

confidence: 99%

Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation

Wang¹,

Matte-Martone

et al. 2011

Blood

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“…Intercellular exchange of MHC molecules has been reported between many cells, including professional and nonprofessional APCs (30,42). However, MHC acquisition by DCs may be of most relevance especially in the context of infection and transplantation.…”

Section: Figure 9 T Cell Activation By Cd8␣mentioning

confidence: 99%

The Relative Efficiency of Acquisition of MHC:Peptide Complexes and Cross-Presentation Depends on Dendritic Cell Type

Smyth

Harker

Turnbull

et al. 2008

The Journal of Immunology

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Intercellular exchange of MHC molecules has been reported between many cells, including professional and nonprofessional APCs. This phenomenon may contribute to T cell immunity to pathogens. In this study, we addressed whether the transfer of MHC class I:peptide complexes between cells plays a role in T cell responses and compare this to conventional cross-presentation. We observed that dsRNA-matured bone marrow-derived dendritic cells (BMDCs) acquired peptide:MHC complexes from other BMDCs either pulsed with OVA257–264 peptide, soluble OVA, or infected with a recombinant adenovirus expressing OVA. In addition, BMDCs were capable of acquiring MHC:peptide complexes from epithelial cells. Spleen-derived CD8α+ and CD8α− dendritic cells (DCs) also acquired MHC:peptide complexes from BMDCs pulsed with OVA257–264 peptide. However, the efficiency of acquisition by these ex vivo derived DCs is much lower than acquisition by BMDC. In all cases, the acquired MHC:peptide complexes were functional in that they induced Ag-specific CD8+ T cell proliferation. The efficiency of MHC transfer was compared with cross-presentation for splenic CD8α+ and CD8α− as well as BMDCs. CD8α+ DCs were more efficient at inducing T cell proliferation when they acquired Ag via cross-presentation, the opposite was observed for BMDCs and splenic CD8α− DCs. We conclude from these observations that the relative efficiency of MHC transfer vs cross-presentation differs markedly between different DC subsets.

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“…More recent studies suggest that host DC also acquire intact donor MHC molecules for presentation to crolimus and mycophenolate mofetil. This generalized immunosuppression predisposes the host to serious in-T cells, the so-called semidirect pathway (39). Indirect responses, while generally thought to be weaker than fections and cancer (19).…”

Section: Introductionmentioning

confidence: 99%

Selective Depletion of Cross-Presenting Dendritic Cells Enhances Islet Allograft Survival

et al. 2011

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MHC class I presentation of peptides derived from exogenous antigens (not synthesized within the antigenpresenting cell) is called cross-presentation and is mediated by selective subsets of dendritic cells (DC). A proportion of both donor and host DC may cross-present. Although there has been many studies that have investigated the role of donor versus host DC (i.e., direct vs. indirect pathway), what role cross-presenting DC play in allograft rejection has not been determined. We recently identified an agent, cytochrome c (cytc), that selectively depletes cross-presenting DC in vivo. By administering cytc we were able to study the impact of cross-presenting DC on rejection of islets grafted into fully mismatched mice. We found that cytc protected about half of the islet allografts from rejection. Our results indicate that cross-presenting DC can make potent contributions to the immune response to islet allografts, and contend that agents such as cytc that selectively target DC heralds a novel method of immunosuppression.

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A Novel Pathway of Antigen Presentation by Dendritic and Endothelial Cells: Implications for Allorecognition and Infectious Diseases

Cited by 75 publications

References 38 publications

Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation

Mechanisms of antigen presentation to T cells in murine graft-versus-host disease: cross-presentation and the appearance of cross-presentation

The Relative Efficiency of Acquisition of MHC:Peptide Complexes and Cross-Presentation Depends on Dendritic Cell Type

Selective Depletion of Cross-Presenting Dendritic Cells Enhances Islet Allograft Survival

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