MHC-dependent desensitization of intrinsic anti-self reactivity

Abstract

The survival of naïve 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 naïve 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 naïve 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.

Dynamic Tuning of Lymphocytes: Physiological Basis, Mechanisms, and Function

“…The authors showed that the CD4 + T cells were hyperresponsive to TCR-mediated stimuli in vitro, implying a reduced level of tuning. Additional evidence that spMHC interactions restrain autoimmunity by tuning was provided by transfer of naive T cells into mice lacking both MHC-I and MHC-II (74). These cells acquired the capacity to reject subsequently transplanted wild-type pancreatic islets or transplantable tumors.…”

Mesenchymal stromal cells inhibit murine syngeneic anti-tumor immune responses by attenuating inflammation and reorganizing the tumor microenvironment

“…LL3 cells were obtained from ATCC (Manassas, VA) and maintained in culture as described [9]. Parental LL3 cells were modified to express firefly luciferase (Luc) and green fluorescent protein (GPF) using the Sleeping Beauty transposon system [19].…”

“…Clinically significant anti-tumor immunity can be reliably generated by delivering Fas ligand (FasL) locally into the tumor environment using replication-deficient adenovirus (Ad) vectors [1-5]. While the ectopically expressed FasL promotes destruction of the primary tumor through an innate response mediated by infiltrating macrophages and neutrophils [1, 6-8], the response to distant tumors is T cell dependent [5, 7, 9]. A unique aspect of Ad-FasL based immunotherapy is that efficacy is not dependent on Fas receptor (CD95) expression by tumor cells.…”

“…Antigen presentation then leads to the activation of tumor specific cytolytic T cells, which are the ultimate effectors that target metastatic disease distant to the site of FasL administration. Ad-FasL thereby triggers a systemic effect that allows expansion of tumor specific T cells, limiting local recurrence and distant metastasis [5, 7, 9, 12]. Experimentally, this response can be evaluated by adoptive transfer [9], while clinically the response can be assessed based on prevention or delay of disease progression, including metastasis and relapse [2].…”

“…It was encouraging that an effective response was achievable in such a large percentage of treated dogs, and this compared favorably with the approximate 7-15% of tumor-bearing rodents where there is tumor “escape” and progression after treatment with Ad-FasL [1, 9]. However, an immunosuppressive barrier might have diminished the capacity of immune effector cells to activate and expand, to migrate into the tumor, or to recognize tumor cells and kill them in the animals where a treatment effect was not observed.…”