The clinical extent of psoriasis pathology is regulated in part by defects in immune networks, including a defect in the suppressive actions of regulatory T cells. Recently, CD14(+) HLA-DR(-/low) monocytic myeloid-derived suppressor cells (Mo-MDSCs) have been shown to suppress T-cell activation as one of their suppressive mechanisms. However, little is known about the role of Mo-MDSCs and their functional relationship to T-cell suppression in relation to human chronic immune-mediated inflammatory diseases, including psoriasis. Despite psoriasis being a hyperinflammatory condition, Mo-MDSCs were elevated in psoriatic patient peripheral blood mononuclear cells compared to nonpsoriatic healthy controls (2.6% vs. 0.9%, P < 0.002). Freshly isolated psoriatic Mo-MDSCs directly suppressed CD8 T-cell proliferation less efficiently than healthy control Mo-MDSCs. In addition, psoriatic Mo-MDSCs expressed reduced surface expression of programmed cell death protein 1 compared to healthy controls. Additional in vitro assays also demonstrated that psoriatic and control Mo-MDSCs both induce regulatory T-cell conversion from naïve T effector cells, but, importantly, the regulatory T cells induced by psoriatic Mo-MDSCs displayed decreased suppressive functionality. These results suggest that aberrations in psoriatic Mo-MDSCs prevent proper suppression of effector T-cell expansion and hamper the immune system's ability to correctly self-regulate.
Bilateral and unilateral UM patients share similar demographics, clinicopathological characteristics, treatments and prognoses. Moreover, the development of bilateral disease does not portend a poorer prognosis and patients should be treated similarly to those with unilateral disease.
Background
Liver parenchymal cell allografts initiate both CD4-dependent and CD4-independent, CD8+ T cell-mediated acute rejection pathways. The magnitude of allospecific CD8+ T cell in vivo cytotoxic effector function is maximal when primed in the presence of CD4+ T cells. The current studies were conducted to determine if and how CD4+ T cells might influence cytotoxic effector mechanisms.
Methods
Mice were transplanted with allogeneic hepatocytes. In vivo cytotoxicity assays and various gene-deficient recipient mice and target cells were utilized to determine the development of Fas-, TNF-α-, and perforin-dependent cytotoxic effectors mechanisms following transplantation.
Results
CD8+ T cells maturing in CD4-sufficient hepatocyte recipients develop multiple (Fas-, TNF-α-, and perforin-mediated) cytotoxic mechanisms. However, CD8+ T cells, maturing in the absence of CD4+ T cells, mediate cytotoxicity and transplant rejection that is exclusively TNF-α/TNFR-dependent. To determine the kinetics of CD4-mediated help, CD4+ T cells were adoptively transferred into CD4-deficient mice at various times posttransplant. The maximal influence of CD4+ T cells on the magnitude of CD8-mediated in vivo allocytotoxicity occurs within 48 hours.
Conclusion
The implication of these studies is that interference of CD4+ T cell function by disease or immunotherapy will have downstream consequences on both the magnitude of allocytotoxicity as well as the cytotoxic effector mechanisms employed by allospecific CD8+ cytolytic T cells.
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