ABSTRACT
The survival of naive T cells is compromised in the absence of molecules encoded by the major histocompatibility complex (MHC) while antigen-experienced T cells survive. We hypothesized that survival pressures in an in vivo, MHC-deficient environment would permit enrichment of less frequent antigen-experienced autoreactive cells at the expense of the majority of antigen naive T cells. To test this hypothesis, we generated MHC class I- and class II-deficient mice in NOD and C57Bl/6 (B6) backgrounds, and examined the capacity of adoptively transferred autoimmune-prone NOD T cells, or non-autoimmune prone naive B6 T cells, respectively, to reject transplanted wild-type pancreatic islets or transplantable tumors in the MHC-deficient mice. In the MHC-deficient environment, CD4 T cells acquired self-hostile properties (islet rejection and tumor invasion) that were independent from their genetic propensity for autoreactivity, while CD8 T cells required appropriate prior exposure to antigen in order to survive and function (reject tumor) in this environment; however, disengagement of Tob1, a negative regulator of proliferation, led to a reverse phenotype with regard to persistence of CD4 and CD8 T cells in the MHC-deficient environment. Our data suggest that self-peptide/MHC interactions have dual roles to facilitate survival and restrain autoreactivity, thus acting as integral components of an intrinsic network of negative regulation that maintains tolerance.
Subject(s)
Autoimmunity , Desensitization, Immunologic , Major Histocompatibility Complex/genetics , Major Histocompatibility Complex/immunology , Animals , CD4-Positive T-Lymphocytes/physiology , CD8-Positive T-Lymphocytes/physiology , Carrier Proteins/metabolism , Cell Line, Tumor , Cell Survival , Immune Tolerance , Intracellular Signaling Peptides and Proteins , Islets of Langerhans/immunology , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , Mice, Knockout , Mice, SCIDABSTRACT
OBJECTIVE: Two competing hypotheses can be formulated regarding the origin of canine hemangiosarcoma (HSA). One states HSA originates from differentiated vascular endothelial cells that undergo mutations which endow them with malignant potential. The other states HSA originates from transformed hemangioblastic stem cells. This study was designed to begin to distinguish between these possibilities, as well as to test if flow cytometry was sufficiently sensitive to detect malignant cells in blood samples from dogs with HSA. METHODS: We used multiparameter flow cytometry to examine expression of cell-surface determinants associated with hematopoietic precursors (c-kit, CD34, CD133, CD45) or with lineage-committed cells (CD3, CD11b, CD14, CD21, CD105, CD146, alphavbeta3-integrin) in HSA cell lines and in blood samples from healthy dogs or dogs with HSA. RESULTS: The data show that HSA cells coexpress surface markers associated with hematopoietic precursors and with commitment to endothelial lineage, providing a means to identify their presence in circulation and distinguish them from normal or malignant white blood cells. The percentage of cells that coexpressed these markers ranged from 0.5 to 1.25% for HSA dogs, and was less than 0.3% for unaffected dogs or dogs with HSA that had the tumors removed within 48 hours prior to obtaining samples. CONCLUSIONS: The results place the ontogeny of HSA with multipotential bone marrow-derived stem cells whose progeny arrest differentiation at the hemangioblast or angioblast stage. In addition, these expression patterns may assist to confirm an HSA diagnosis, monitor minimal residual disease, and detect the disease in early stages.
