Donor-derived exosomes: the trick behind the semidirect pathway of allorecognition

Purpose of review The passenger leukocyte hypothesis predicts that after transplantation, donor antigen-presenting cells (APCs) from the graft present donor MHC molecules to directly alloreactive T cells in lymphoid organs. However, in certain transplantation models, recent evidence contradicts this long-standing concept. New findings demonstrate that host, instead of donor, APCs play a prominent role in allosensitization against donor MHC molecules via the semidirect pathway. A similar mechanism operates in development of T-cell split tolerance to noninherited maternal antigens. Recent findings Following fully mismatch skin or heart transplantation in mice, no or extremely few donor migrating APCs (i.e. conventional dendritic cells) are detected in the draining lymphoid organs. Instead, recipient dendritic cells that have captured donor extracellular vesicles (i.e. exosomes) carrying donor MHC molecules and APC costimulatory signals present donor MHC molecules to directly alloreactive T cells. This semidirect pathway can also give rise to a form of ‘split’ tolerance during chronic alloantigen exposure, as indirectly alloreactive T helper cells and directly alloreactive T-cell effectors are differentially impacted by host dendritic cells ‘cross-dressed’ with extracellular vesicles/exosomes derived from maternal microchimerism. Summary Acquisition by recipient APCs of donor exosomes (and likely other extracellular vesicles) released by passenger leukocytes or the graft explains the potent T-cell allosensitization against donor MHC molecules, in the absence or presence of few passenger leukocytes in lymphoid organs. It also provides the basic mechanism and in-vivo relevance of the elusive semidirect pathway. Its degree of coordination with the allopeptide – specific, indirect pathway of T-cell help may determine whether semidirect allopresentation results in a sustained, effective, acute rejection response, or rather, in abortive acute rejection and ‘split’ tolerance.

[1]  T. Mohanakumar,et al.  Donor‐Derived Exosomes With Lung Self‐Antigens in Human Lung Allograft Rejection , 2017, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  K. Dou,et al.  Combining Exosomes Derived from Immature DCs with Donor Antigen-Specific Treg Cells Induces Tolerance in a Rat Liver Allograft Model , 2016, Scientific Reports.

[3]  J. Ge,et al.  Exosomes derived from mature dendritic cells increase endothelial inflammation and atherosclerosis via membrane TNF‐α mediated NF‐κB pathway , 2016, Journal of cellular and molecular medicine.

[4]  Simon C Watkins,et al.  Donor dendritic cell-derived exosomes promote allograft-targeting immune response. , 2016, The Journal of clinical investigation.

[5]  F. Vannberg,et al.  Lymphatic transport of exosomes as a rapid route of information dissemination to the lymph node , 2016, Scientific Reports.

[6]  F. Ginhoux,et al.  The Mononuclear Phagocyte System in Organ Transplantation , 2016, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  T. Ochiya,et al.  Extracellular vesicle transfer of cancer pathogenic components , 2016, Cancer science.

[8]  M. Ratajczak,et al.  Horizontal transfer of RNA and proteins between cells by extracellular microvesicles: 14 years later , 2016, Clinical and Translational Medicine.

[9]  R. Simpson,et al.  Podoplanin is a component of extracellular vesicles that reprograms cell-derived exosomal proteins and modulates lymphatic vessel formation , 2016, Oncotarget.

[10]  C. Théry,et al.  Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes , 2016, Proceedings of the National Academy of Sciences.

[11]  R. Christopherson,et al.  Extensive surface protein profiles of extracellular vesicles from cancer cells may provide diagnostic signatures from blood samples , 2016, Journal of extracellular vesicles.

[12]  A. Lau,et al.  The 20S proteasome core, active within apoptotic exosome-like vesicles, induces autoantibody production and accelerates rejection , 2015, Science Translational Medicine.

[13]  Olivier Lantz,et al.  Dendritic cell-derived exosomes as maintenance immunotherapy after first line chemotherapy in NSCLC , 2015, Oncoimmunology.

[14]  Tony T. Jiang,et al.  Cross-Generational Reproductive Fitness Enforced by Microchimeric Maternal Cells , 2015, Cell.

[15]  D. Kaufman,et al.  Patterns of Immune Regulation in Rhesus Macaque and Human Families , 2015, Transplantation direct.

[16]  Christopher H Contag,et al.  Differential fates of biomolecules delivered to target cells via extracellular vesicles , 2015, Proceedings of the National Academy of Sciences.

[17]  George A Calin,et al.  Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. , 2014, Cancer cell.

[18]  C. Théry,et al.  Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. , 2014, Annual review of cell and developmental biology.

[19]  G. Hill,et al.  Cross-Dressing by Donor Dendritic Cells after Allogeneic Bone Marrow Transplantation Contributes to Formation of the Immunological Synapse and Maximizes Responses to Indirectly Presented Antigen , 2014, The Journal of Immunology.

[20]  P. Robbins,et al.  Regulation of immune responses by extracellular vesicles , 2014, Nature Reviews Immunology.

[21]  A. Morelli Dendritic cells of myeloid lineage: the masterminds behind acute allograft rejection , 2014, Current opinion in organ transplantation.

[22]  Andrew F. Hill,et al.  Minimal experimental requirements for definition of extracellular vesicles and their functions: a position statement from the International Society for Extracellular Vesicles , 2014, Journal of extracellular vesicles.

[23]  Imre Mäger,et al.  Extracellular vesicles: biology and emerging therapeutic opportunities , 2013, Nature Reviews Drug Discovery.

[24]  Simon C Watkins,et al.  Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes. , 2012, Blood.

[25]  P. Dutta,et al.  Correlation between post transplant maternal microchimerism and tolerance across MHC barriers in mice , 2011, Chimerism.

[26]  K. Brown,et al.  Coexpression of Donor Peptide/Recipient MHC Complex and Intact Donor MHC: Evidence for a Link between the Direct and Indirect Pathways , 2011, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[27]  Fátima Sánchez-Cabo,et al.  Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells , 2011, Nature communications.

[28]  M. Cahalan,et al.  NK Cell Patrolling and Elimination of Donor-Derived Dendritic Cells Favor Indirect Alloreactivity , 2010, The Journal of Immunology.

[29]  J. Smits,et al.  Reexposure of cord blood to noninherited maternal HLA antigens improves transplant outcome in hematological malignancies , 2009, Proceedings of the National Academy of Sciences.

[30]  P. Dutta,et al.  Microchimerism is strongly correlated with tolerance to noninherited maternal antigens in mice. , 2009, Blood.

[31]  Jeff E. Mold,et al.  Maternal Alloantigens Promote the Development of Tolerogenic Fetal Regulatory T Cells in Utero , 2008, Science.

[32]  K. Brown,et al.  Extensive and bidirectional transfer of major histocompatibility complex class II molecules between donor and recipient cells in vivo following solid organ transplantation , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[33]  J. Ortaldo,et al.  Natural killer cells recruited into lymph nodes inhibit alloreactive T-cell activation through perforin-mediated killing of donor allogeneic dendritic cells. , 2008, Blood.

[34]  Simon C Watkins,et al.  Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition1 , 2008, The Journal of Immunology.

[35]  J. Lötvall,et al.  Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells , 2007, Nature Cell Biology.

[36]  C. Demur,et al.  CD8+ T-cell-mediated killing of donor dendritic cells prevents alloreactive T helper type-2 responses in vivo. , 2006, Blood.

[37]  X. Li,et al.  NK cells promote transplant tolerance by killing donor antigen-presenting cells , 2006, The Journal of experimental medicine.

[38]  C. Théry,et al.  ICAM-1 on exosomes from mature dendritic cells is critical for efficient naive T-cell priming. , 2005, Blood.

[39]  R. Lechler,et al.  A Novel Pathway of Alloantigen Presentation by Dendritic Cells1 , 2004, The Journal of Immunology.

[40]  R. Lechler,et al.  New spectrum of allorecognition pathways: implications for graft rejection and transplantation tolerance. , 2004, Current opinion in immunology.

[41]  F. Claas,et al.  Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or an HLA-haploidentical sibling. , 2002, Blood.

[42]  G. Opelz The effect of tolerance to noninherited maternal HLA antigens on the survival of renal transplants from sibling donors. , 1999, The New England journal of medicine.

[43]  D. Roelen,et al.  No evidence of an influence of the noninherited maternal HLA antigens on the alloreactive T cell repertoire in healthy individuals. , 1995, Transplantation.

[44]  Richard G. Miller,et al.  THE CORRELATION OF PROLONGED SURVIVAL OF MATERNAL SKIN GRAFTS WITH THE PRESENCE OF NATURALLY TRANSFERRED MATERNAL T CELLS , 1993, Transplantation.

[45]  T. Mohanakumar,et al.  Lack of T-cell tolerance of noninherited maternal HLA antigens in normal humans. , 1990, Human immunology.

[46]  J. Markmann,et al.  Donor exosomes rather than passenger leukocytes initiate alloreactive T cell responses after transplantation. , 2016, Science immunology.