RESUMO
Solid organ transplantation remains the life-saving treatment for end-stage organ failure, but chronic rejection remains a major obstacle to long-term allograft outcomes and has not improved substantially. Tertiary lymphoid organs (TLOs) are ectopic lymphoid structures that form under conditions of chronic inflammation, and evidence from human transplantation suggests that TLOs regularly form in allografts undergoing chronic rejection. In this study, we utilized a mouse renal transplantation model and manipulation of the lymphotoxin αß/lymphotoxin ß receptor (LTαß/LTßR) pathway, which is essential for TLO formation, to define the role of TLOs in transplantation. We showed that intragraft TLOs are sufficient to activate the alloimmune response and mediate graft rejection in a model where the only lymphoid organs are TLOs in the allograft. When transplanted to recipients with a normal set of secondary lymphoid organs, the presence of graft TLOs or LTα overexpression accelerated rejection. If the LTßR pathway was disrupted in the donor graft, TLO formation was abrogated, and graft survival was prolonged. Intravital microscopy of renal TLOs demonstrated that local T and B cell activation in TLOs is similar to that observed in secondary lymphoid organs. In summary, we demonstrated that immune activation in TLOs contributes to local immune responses, leading to earlier allograft failure. TLOs and the LTαß/LTßR pathway are therefore prime targets to limit local immune responses and prevent allograft rejection. These findings are applicable to other diseases, such as autoimmune diseases or tumors, where either limiting or boosting local immune responses is beneficial and improves disease outcomes.
Assuntos
Rejeição de Enxerto , Transplante de Rim , Receptor beta de Linfotoxina , Estruturas Linfoides Terciárias , Animais , Receptor beta de Linfotoxina/metabolismo , Receptor beta de Linfotoxina/genética , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Camundongos , Estruturas Linfoides Terciárias/imunologia , Estruturas Linfoides Terciárias/patologia , Aloenxertos/imunologia , Camundongos Endogâmicos C57BL , Sobrevivência de Enxerto/imunologia , Masculino , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Humanos , Transplante HomólogoRESUMO
Our understanding of tissue-resident memory T (TRM) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about TRM cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie TRM maintenance in a kidney transplantation model in which TRM cells drive rejection. In contrast to acute infection, we found that TRM cells declined markedly in the absence of cognate antigen, antigen presentation, or antigen sensing by the T cells. Depletion of graft-infiltrating dendritic cells or interruption of antigen presentation after TRM cells were established was sufficient to disrupt TRM maintenance and reduce allograft pathology. Likewise, removal of IL-15 transpresentation or of the IL-15 receptor on T cells during TRM maintenance led to a decline in TRM cells, and IL-15 receptor blockade prevented chronic rejection. Therefore, antigen and IL-15 presented by dendritic cells play nonredundant key roles in CD8 TRM cell maintenance in settings of antigen persistence and inflammation. These findings provide insights that could lead to improved treatment of chronic transplant rejection and autoimmunity.
Assuntos
Linfócitos T CD8-Positivos , Interleucina-15 , Humanos , Antígenos , Inflamação , Células T de MemóriaRESUMO
In allogeneic hematopoietic stem cell transplantation, donor αß T cells attack recipient tissues, causing graft-versus-host disease (GVHD), a major cause of morbidity and mortality. A central question has been how GVHD is sustained despite T cell exhaustion from chronic antigen stimulation. The current model for GVHD holds that disease is maintained through the continued recruitment of alloreactive effectors from blood into affected tissues. Here, we show, using multiple approaches including parabiosis of mice with GVHD, that GVHD is instead primarily maintained locally within diseased tissues. By tracking 1,203 alloreactive T cell clones, we fitted a mathematical model predicting that within each tissue a small number of progenitor T cells maintain a larger effector pool. Consistent with this, we identified a tissue-resident TCF-1+ subpopulation that preferentially engrafted, expanded, and differentiated into effectors upon adoptive transfer. These results suggest that therapies targeting affected tissues and progenitor T cells within them would be effective.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Camundongos , Animais , Linfócitos T , Transplante Homólogo/efeitos adversos , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodosRESUMO
Major histocompatibility complex I (MHC-I) molecules present epitopes on the cellular surface of antigen-presenting cells to prime cytotoxic clusters of differentiation 8 (CD8)+ T cells (CTLs), which then identify and eliminate other cells such as virus-infected cells bearing the antigen. Human hepatitis virus cohort studies have previously identified MHC-I molecules as promising predictors of viral clearance. However, the underlying functional significance of these predictions is not fully understood. Here, we show that expression of single MHC-I isomers promotes virus-induced liver immunopathology. Specifically, using the lymphocytic choriomeningitis virus (LCMV) model system, we found MHC-I proteins to be highly up-regulated during infection. Deletion of one of the two MHC-I isomers histocompatibility antigen 2 (H2)-Db or H2-Kb in C57Bl/6 mice resulted in CTL activation recognizing the remaining MHC-I with LCMV epitopes in increased paucity. This increased CTL response resulted in hepatocyte death, increased caspase activation, and severe metabolic changes in liver tissue following infection with LCMV. Moreover, depletion of CTLs abolished LCMV-induced pathology in these mice with resulting viral persistence. In turn, natural killer (NK) cell depletion further increased antiviral CTL immunity and clearance of LCMV even in the presence of a single MHC-I isomer. Conclusion: Our results suggest that uniform MHC-I molecule expression promotes enhanced CTL immunity during viral infection and contributes to increased CTL-mediated liver cell damage that was alleviated by CD8 or NK cell depletion.
Assuntos
Coriomeningite Linfocítica , Animais , Epitopos , Antígenos de Histocompatibilidade , Humanos , Fígado , Coriomeningite Linfocítica/genética , Vírus da Coriomeningite Linfocítica/genética , Complexo Principal de Histocompatibilidade , CamundongosRESUMO
BACKGROUND: Allergic contact dermatitis (CD) is a chronic inflammatory skin disease caused by type 1 biased adaptive immunity for which there is an unmet need for antigen (Ag)-specific immunotherapies. Exposure to skin sensitizers stimulates secretion of the proinflammatory neuropeptides substance P and hemokinin 1, which signal via the neurokinin-1 receptor (NK1R) to promote the innate and adaptive immune responses of CD. Accordingly, mice lacking the NK1R develop impaired CD. Nonetheless, the role and therapeutic opportunities of targeting the NK1R in CD remain to be elucidated. OBJECTIVE: We sought to develop an Ag-specific immunosuppressive approach to treat CD by skin codelivery of hapten and NK1R antagonists integrated in dissolvable microneedle arrays (MNA). METHODS: In vivo mouse models of contact hypersensitivity and ex vivo models of human skin were used to delineate the effects and mechanisms of NK1R signaling and the immunosuppressive effects of the contact sensitizer NK1R antagonist MNA in CD. RESULTS: We demonstrated in mice that CD requires NK1R signaling by substance P and hemokinin 1. Specific deletion of the NK1R in keratinocytes and dendritic cells, but not in mast cells, prevented CD. Skin codelivery of hapten or Ag MNA inhibited neuropeptide-mediated skin inflammation in mouse and human skin, promoted deletion of Ag-specific effector T cells, and increased regulatory T cells, which prevented CD onset and relapses locally and systemically in an Ag-specific manner. CONCLUSIONS: Immunoregulation by engineering localized skin neuroimmune networks can be used to treat cutaneous diseases that like CD are caused by type 1 immunity.
Assuntos
Dermatite Alérgica de Contato , Antagonistas dos Receptores de Neurocinina-1 , Animais , Dermatite Alérgica de Contato/tratamento farmacológico , Haptenos , Camundongos , Antagonistas dos Receptores de Neurocinina-1/farmacologia , Receptores da Neurocinina-1 , Substância PRESUMO
Successful allogeneic transplantation has been made possible by suppressing activation of the adaptive immune system. Current immunosuppressive therapy prevents rejection by targeting T and B cells. Despite this effective treatment, it is the innate immune system, which includes dendritic cells, monocytes, natural killer cells, that is responsible for the initiation of the adaptive immune response. Recent work has described that the innate immune system is capable of recognizing allogeneic nonself and some of the mechanisms of innate allorecognition have been uncovered. Better understanding of the role of the innate immune system in initiation and maintenance of the allo-immune response has potential to lead to better treatment strategies for transplant patients, prolonging allograft survival. Here, we review advances in our understanding of innate allorecognition in transplantation.
Assuntos
Rejeição de Enxerto/imunologia , Imunidade Inata/imunologia , Transplante de Órgãos , Humanos , Transplante HomólogoRESUMO
Despite the role of donor-specific antibodies (DSAs) in recognizing major histocompatibility complex (MHC) antigens and mediating transplant rejection, how and where recipient B cells in lymphoid tissues encounter donor MHC antigens remains unclear. Contrary to the dogma, we demonstrated here that migration of donor leukocytes out of skin or heart allografts is not necessary for B or T cell allosensitization in mice. We found that mouse skin and cardiac allografts and human skin grafts release cell-free donor MHC antigens via extracellular vesicles (EVs) that are captured by subcapsular sinus (SCS) macrophages in lymph nodes or analog macrophages in the spleen. Donor EVs were transported across the SCS macrophages, and donor MHC molecules on the EVs were recognized by alloreactive B cells. This triggered B cell activation and DSA production, which were both prevented by SCS macrophage depletion. These results reveal an unexpected role for graft-derived EVs and open venues to interfere with EV biogenesis, trafficking, or function to restrain priming or reactivation of alloreactive B cells.
Assuntos
Vesículas Extracelulares , Transplante de Coração , Animais , Linfócitos B , Rejeição de Enxerto , Macrófagos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BLRESUMO
Tissue-resident memory T cells (TRM) contained at sites of previous infection provide local protection against reinfection. Whether they form and function in organ transplants where cognate antigen persists is unclear. This is a key question in transplantation as T cells are detected long term in allografts, but it is not known whether they are exhausted or are functional memory T cells. Using a mouse model of kidney transplantation, we showed that antigen-specific and polyclonal effector T cells differentiated in the graft into TRM and subsequently caused allograft rejection. TRM identity was established by surface phenotype, transcriptional profile, and inability to recirculate in parabiosis and retransplantation experiments. Graft TRM proliferated locally, produced interferon-γ upon restimulation, and their in vivo depletion attenuated rejection. The vast majority of antigen-specific and polyclonal TRM lacked phenotypic and transcriptional exhaustion markers. Single-cell analysis of graft T cells early and late after transplantation identified a transcriptional program associated with transition to the tissue-resident state that could serve as a platform for the discovery of therapeutic targets. Thus, recipient effector T cells differentiate into functional graft TRM that maintain rejection locally. Targeting these TRM could improve renal transplant outcomes.
Assuntos
Aloenxertos/imunologia , Antígenos/imunologia , Rejeição de Enxerto/imunologia , Memória Imunológica , Células T de Memória/imunologia , Aloenxertos/metabolismo , Aloenxertos/patologia , Animais , Biomarcadores , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Modelos Animais de Doenças , Rejeição de Enxerto/metabolismo , Rejeição de Enxerto/patologia , Imuno-Histoquímica , Imunofenotipagem , Transplante de Rim , Células T de Memória/metabolismo , Camundongos , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologiaRESUMO
Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.
Assuntos
Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Coração/efeitos adversos , Interleucina-33/imunologia , Macrófagos/imunologia , Alarminas/imunologia , Aloenxertos , Animais , Criança , Modelos Animais de Doenças , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto/imunologia , Humanos , Interleucina-33/administração & dosagem , Interleucina-33/deficiência , Interleucina-33/genética , Ativação de Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Miocárdio/imunologia , Miocárdio/patologia , Regulação para CimaRESUMO
Over the past few decades, we have witnessed a decline in the rates of acute rejection without significant improvement in chronic rejection. Current treatment strategies principally target the adaptive immune response and not the innate response. Therefore, better understanding of innate immunity in transplantation and how to target it is highly desirable. Here, we review the latest advances in innate immunity in transplantation focusing on the roles and mechanisms of innate allorecognition and memory in myeloid cells. These novel concepts could explain why alloimmune response do not abate over time and shed light on new molecular pathways that can be interrupted to prevent or treat chronic rejection.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Imunidade Inata , Memória Imunológica , Isoantígenos/imunologia , Transplante de Órgãos/efeitos adversos , Tolerância ao Transplante , Animais , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Memória Imunológica/efeitos dos fármacos , Imunossupressores/uso terapêutico , Tolerância ao Transplante/efeitos dos fármacos , Resultado do TratamentoRESUMO
Immunological memory specific to previously encountered antigens is a cardinal feature of adaptive lymphoid cells. However, it is unknown whether innate myeloid cells retain memory of prior antigenic stimulation and respond to it more vigorously on subsequent encounters. In this work, we show that murine monocytes and macrophages acquire memory specific to major histocompatibility complex I (MHC-I) antigens, and we identify A-type paired immunoglobulin-like receptors (PIR-As) as the MHC-I receptors necessary for the memory response. We demonstrate that deleting PIR-A in the recipient or blocking PIR-A binding to donor MHC-I molecules blocks memory and attenuates kidney and heart allograft rejection. Thus, innate myeloid cells acquire alloantigen-specific memory that can be targeted to improve transplant outcomes.
Assuntos
Rejeição de Enxerto/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Imunidade Inata , Memória Imunológica , Macrófagos/imunologia , Monócitos/imunologia , Receptores Imunológicos/fisiologia , Animais , Deleção de Genes , Rejeição de Enxerto/genética , Transplante de Coração , Transplante de Rim , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Mutantes , Receptores Imunológicos/genéticaRESUMO
Activation of host T cells that mediate allograft rejection is a 2-step process. The first occurs in secondary lymphoid organs where T cells encounter alloantigens presented by host DCs and differentiate to effectors. Antigen presentation at these sites occurs principally via transfer of intact, donor MHC-peptide complexes from graft cells to host DCs (cross-dressing) or by uptake and processing of donor antigens into allopeptides bound to self-MHC molecules (indirect presentation). The second step takes place in the graft, where effector T cells reengage with host DCs before causing rejection. How host DCs present alloantigens to T cells in the graft is not known. Using mouse islet and kidney transplantation models, imaging cytometry, and 2-photon intravital microscopy, we demonstrate extensive cross-dressing of intragraft host DCs with donor MHC-peptide complexes that occurred early after transplantation, whereas host DCs presenting donor antigen via the indirect pathway were rare. Cross-dressed DCs stably engaged TCR-transgenic effector CD8+ T cells that recognized donor antigen and were sufficient for sustaining acute rejection. In the chronic kidney rejection model, cross-dressing declined over time but was still conspicuous 8 weeks after transplantation. We conclude that cross-dressing of host DCs with donor MHC molecules is a major antigen presentation pathway driving effector T cell responses within allografts.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Transplante de Rim , Ativação Linfocitária , Aloenxertos , Animais , Linfócitos T CD8-Positivos/patologia , Células Dendríticas/patologia , Rejeição de Enxerto/patologia , Camundongos , Camundongos Knockout , Imunologia de TransplantesRESUMO
Kidney transplantation is the treatment of choice for ESRD but is complicated by the response of the recipient's immune system to nonself histocompatibility antigens on the graft, resulting in rejection. Multiphoton intravital microscopy, referred to as four-dimensional imaging because it records dynamic events in three-dimensional tissue volumes, has emerged as a powerful tool to study immunologic processes in living animals. Here, we will review advances in understanding the complex mechanisms of T cell-mediated rejection made possible by four-dimensional imaging of mouse renal allografts. We will summarize recent data showing that activated (effector) T cell migration to the graft is driven by cognate antigen presented by dendritic cells that surround and penetrate peritubular capillaries, and that T cell-dendritic cell interactions persist in the graft over time, maintaining the immune response in the tissue.
Assuntos
Rejeição de Enxerto/diagnóstico por imagem , Microscopia Intravital/métodos , Microscopia de Fluorescência por Excitação Multifotônica , Linfócitos T/imunologia , Linfócitos T/patologia , Animais , Movimento Celular , Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , CamundongosRESUMO
Mice devoid of T, B, and natural killer (NK) cells distinguish between self and allogeneic nonself despite the absence of an adaptive immune system. When challenged with an allograft, they mount an innate response characterized by accumulation of mature, monocyte-derived dendritic cells (DCs) that produce interleukin-12 and present antigen to T cells. However, the molecular mechanisms by which the innate immune system detects allogeneic nonself to generate these DCs are not known. To address this question, we studied the innate response of Rag2-/- γc-/- mice, which lack T, B, and NK cells, to grafts from allogeneic donors. By positional cloning, we identified that donor polymorphism in the gene encoding signal regulatory protein α (SIRPα) is a key modulator of the recipient's innate allorecognition response. Donors that differed from the recipient in one or both Sirpa alleles elicited an innate alloresponse. The response was mediated by binding of donor SIRPα to recipient CD47 and was modulated by the strength of the SIRPα-CD47 interaction. Therefore, sensing SIRPα polymorphism by CD47 provides a molecular mechanism by which the innate immune system distinguishes between self and allogeneic nonself independently of T, B, and NK cells.
RESUMO
Successful engraftment of organ transplants has traditionally relied on preventing the activation of recipient (host) T cells. Once T-cell activation has occurred, however, stalling the rejection process becomes increasingly difficult, leading to graft failure. Here we demonstrate that graft-infiltrating, recipient (host) dendritic cells (DCs) play a key role in driving the rejection of transplanted organs by activated (effector) T cells. We show that donor DCs that accompany heart or kidney grafts are rapidly replaced by recipient DCs. The DCs originate from non-classical monocytes and form stable, cognate interactions with effector T cells in the graft. Eliminating recipient DCs reduces the proliferation and survival of graft-infiltrating T cells and abrogates ongoing rejection or rejection mediated by transferred effector T cells. Therefore, host DCs that infiltrate transplanted organs sustain the alloimmune response after T-cell activation has already occurred. Targeting these cells provides a means for preventing or treating rejection.
Assuntos
Células Dendríticas/imunologia , Rejeição de Enxerto/imunologia , Linfócitos T/imunologia , Animais , Transplante de Coração , Transplante de Rim , Ativação Linfocitária , Camundongos , TransplantesRESUMO
Bony fish are among the first vertebrates to possess an innate and adaptive immune system. In these species, the kidney has a dual function: filtering solutes similar to mammals and acting as a lymphoid organ responsible for hematopoiesis and antigen processing. Recent studies have shown that the mammalian kidney has an extensive network of mononuclear phagocytes, whose function is not fully understood. Here, we employed two-photon intravital microscopy of fluorescent reporter mice to demonstrate that renal dendritic cells encase the microvasculature in the cortex, extend dendrites into the peritubular capillaries, and sample the blood for antigen. We utilized a mouse model of systemic bacterial infection as well as immune complexes to demonstrate antigen uptake by renal dendritic cells. As a consequence, renal dendritic cells mediated T-cell migration into the kidney in an antigen-dependent manner in the setting of bacterial infection. Thus, renal dendritic cells may be uniquely positioned to play an important role not only in surveillance of systemic infection but also in local infection and autoimmunity.
Assuntos
Autoimunidade , Infecções Bacterianas/imunologia , Movimento Celular/imunologia , Células Dendríticas/imunologia , Rim/imunologia , Linfócitos T/fisiologia , Animais , Apresentação de Antígeno/imunologia , Complexo Antígeno-Anticorpo , Células Dendríticas/ultraestrutura , Microscopia Intravital , Rim/irrigação sanguínea , Rim/citologia , Rim/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica , Modelos AnimaisRESUMO
Pancreatic islet transplantation is a promising therapy for diabetes, but acute rejection of the islets by host effector T cells has hindered clinical application. In this study, we addressed the mechanisms of CD8(+) effector T cell migration to islet grafts because interrupting this step is key to preventing rejection. We found that effector T cell migration to revascularized islet transplants in mice is dependent on non-self Ag recognition rather than signaling via Gαi-coupled chemokine receptors. Presentation of non-self Ag by donor cells was necessary for migration, whereas Ag presentation by recipient cells was dispensable. We also observed that deficiency of SKAP1, an immune cell adaptor downstream of the TCR and important for integrin activation, prolongs allograft survival but does not reduce effector T cell migration to the graft. Therefore, effector T cell migration to transplanted islets is Ag driven, not chemokine driven, but SKAP1 does not play a critical role in this process.
Assuntos
Apresentação de Antígeno/imunologia , Linfócitos T CD8-Positivos/imunologia , Quimiotaxia de Leucócito/imunologia , Rejeição de Enxerto/imunologia , Transplante das Ilhotas Pancreáticas/imunologia , Animais , Ilhotas Pancreáticas/imunologia , Camundongos , Modelos AnimaisRESUMO
Maturation of T cell-activating APCs directly links innate and adaptive immunity and is typically triggered by microbial infection. Transplantation of allografts, which are sterile, generates strong T cell responses; however, it is unclear how grafts induce APC maturation in the absence of microbial-derived signals. A widely accepted hypothesis is that dying cells in the graft release "danger" molecules that induce APC maturation and initiate the adaptive alloimmune response. Here, we demonstrated that danger signals associated with dying cells are not sufficient to initiate alloimmunity, but that recognition of allogeneic non-self by the innate immune system is required. In WT as well as in T cell-, B cell-, and innate lymphoid cell-deficient mice, allogeneic grafts elicited persistent differentiation of monocytes into mature DCs that expressed IL-12 and stimulated T cell proliferation and IFN-γ production. In contrast, syngeneic grafts in the same mice elicited transient and less pronounced differentiation of monocytes into DCs, which neither expressed IL-12 nor stimulated IFN-γ production. In a model in which T cell recognition is restricted to a single foreign antigen on the graft, rejection occurred only if the allogeneic non-self signal was also sensed by the host's innate immune system. These findings underscore the importance of innate recognition of allogeneic non-self by monocytes in initiating graft rejection.