ABSTRACT
PURPOSE OF REVIEW: To review the classical paradigm of leukocyte migration and present new evidence that cognate antigen, and not signaling via Gαi-coupled chemokine receptors, drives the migration of effector and memory T cells into vascularized organ transplants. RECENT FINDINGS: Blocking Gαi function does not hinder integrin-dependent T-cell migration to heart and kidney allografts or significantly delay acute rejection. T-cell firm adhesion and transmigration is instead mediated by engagement of the T cell receptor for antigen (TCR) on antigen-specific (antidonor) T cells by cognate antigen presented by either graft endothelial cells or bone marrow-derived antigen-presenting cells that reach into the vascular lumen. Influx of bystander T cells is Gαi-dependent but occurs only if antigen-specific T cells are present. SUMMARY: Antigen-driven migration of effector and memory T cells sheds new light on the pathogenesis of transplant rejection and predicts that interrupting the TCR-triggered 'inside-out' signaling pathway, rather than that initiated by Gαi-coupled chemokine receptors, is a key approach to preventing rejection.
Subject(s)
Allografts/blood supply , Allografts/immunology , Cell Movement/immunology , Heart Transplantation , Kidney Transplantation , T-Lymphocytes/immunology , Animals , Coronary Vessels/immunology , Graft Rejection/immunology , Humans , Kidney/blood supply , Kidney/immunology , Receptors, Antigen, T-Cell , Transplantation, HomologousABSTRACT
The migration of effector or memory T cells to the graft is a critical event in the rejection of transplanted organs. The prevailing view is that the key steps involved in T cell migration - integrin-mediated firm adhesion followed by transendothelial migration - are dependent on the activation of Gαi-coupled chemokine receptors on T cells. In contrast to this view, we demonstrated in vivo that cognate antigen was necessary for the firm adhesion and transendothelial migration of CD8+ effector T cells specific to graft antigens and that both steps occurred independent of Gαi signaling. Presentation of cognate antigen by either graft endothelial cells or bone marrow-derived APCs that extend into the capillary lumen was sufficient for T cell migration. The adhesion and transmigration of antigen-nonspecific (bystander) effector T cells, on the other hand, remained dependent on Gαi, but required the presence of antigen-specific effector T cells. These findings underscore the primary role of cognate antigen presented by either endothelial cells or bone marrow-derived APCs in the migration of T cells across endothelial barriers and have important implications for the prevention and treatment of graft rejection.
Subject(s)
Antigen Presentation , CD8-Positive T-Lymphocytes/physiology , Heart Transplantation/immunology , Kidney Transplantation/immunology , Transendothelial and Transepithelial Migration/immunology , Adoptive Transfer , Animals , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/transplantation , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/transplantation , Cell Adhesion , Coronary Vessels/immunology , Coronary Vessels/pathology , Endothelial Cells/immunology , Endothelial Cells/metabolism , GTP-Binding Protein alpha Subunits, Gi-Go/physiology , Graft Rejection/immunology , Graft Rejection/prevention & control , Immunotherapy, Adoptive , Kidney/blood supply , Kidney/immunology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Microscopy, Fluorescence , Myocardium/immunology , Receptors, Chemokine/physiology , Signal Transduction , Time-Lapse ImagingABSTRACT
BACKGROUND: Memory T cells migrate to and reject transplanted organs without the need for priming in secondary lymphoid tissues, but the mechanisms by which they do so are not known. Here, we tested whether CXCR3, implicated in the homing of effector T cells to sites of infection, is critical for memory T-cell migration to vascularized allografts. METHODS: CD4 and CD8 memory T cells were sorted from alloimmunized CXCR3 and wildtype B6 mice and cotransferred to congenic B6 recipients of BALB/c heart allografts. Graft-infiltrating T cells were quantitated 20 and 72 hr later by flow cytometry. Migration and allograft survival were also studied in splenectomized alymphoplastic (aly/aly) recipients, which lack secondary lymphoid tissues. RESULTS: We found that polyclonal and antigen-specific memory T cells express high levels of CXCR3. No difference in migration of wildtype versus CXCR3 CD4 and CD8 memory T cells to allografts could be detected in wildtype or aly/aly hosts. In the latter, wildtype and CXCR3 memory T cells precipitated acute rejection at similar rates. Blocking CCR5, a chemokine receptor also upregulated on memory T cells, did not delay graft rejection mediated by CXCR3 memory T cells. CONCLUSIONS: CXCR3 is not critical for the migration of memory T cells to vascularized organ allografts. Blocking CXCR3 or CXCR3 and CCR5 does not delay acute rejection mediated by memory T cells. These findings suggest that the mechanisms of memory T cell-homing to transplanted organs may be distinct from those required for their migration to sites of infection.
Subject(s)
Cell Movement , Graft Rejection/immunology , Graft Survival , Heart Transplantation/immunology , Immunologic Memory , Receptors, CXCR3/metabolism , T-Lymphocytes/immunology , Adoptive Transfer , Animals , Cell Adhesion Molecules/metabolism , Flow Cytometry , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Receptors, CCR5/metabolism , Receptors, CXCR3/deficiency , Receptors, CXCR3/genetics , Splenectomy , Time Factors , Transplantation, HomologousABSTRACT
OBJECTIVE: Exposure to natural sunlight has been associated with improvement in mood, reduced mortality among patients with cancer, and reduced length of hospitalization for patients who have experienced myocardial infarction. Our aim was to evaluate whether the amount of sunlight in a hospital room modifies a patient's psychosocial health, the quantity of analgesic medication used, and the pain medication cost. METHODS: A prospective study of pain medication use was conducted in 89 patients undergoing elective cervical and lumbar spinal surgery where they were housed on either the "bright" or "dim" side of the same hospital unit. Analgesic medication was converted to standard morphine equivalents for interpatient comparison. The intensity of sunlight in each hospital room was measured daily and psychologic questionnaires were administered on the day after surgery and at discharge. RESULTS: Patients staying on the bright side of the hospital unit were exposed to 46% higher-intensity sunlight on average (p = .005). Patients exposed to an increased intensity of sunlight experienced less perceived stress (p = .035), marginally less pain (p = .058), took 22% less analgesic medication per hour (p = .047), and had 21% less pain medication costs (p = .047). Age quartile was the only other variable found to be a predictor of analgesic use, with a significant negative correlation (p <.001). However, patients housed on the bright side of the hospital consistently used less analgesic medications in all age quartiles. CONCLUSION: The exposure postoperatively of patients who have undergone spinal surgery to increased amounts of natural sunlight during their hospital recovery period may result in decreased stress, pain, analgesic medication use, and pain medication costs.