HDAC Inhibitors as Epigenetic Regulators

Multiparameter flow cytometric analysis was performed for CD161, CD25, FoxP3, CD127, and Helios in freshly isolated cells or after co-culture for 7 days.A. memory T cells results in T cell activation and EC secretion of IL-6. Neutralizing IL-6 in primary allogeneic T cell-EC co-cultures results in enhanced T cell proliferation of CD161(+) CD4(+) T cells, reduces total T cell proliferation upon restimulation in secondary cultures, an effect dependent on CD161(+) T cells, increases expression of FoxP3 in CD161(+) T cells, and generates T cells that suppress proliferation of freshly isolated T cells. These data suggest that IL-6 released from injured allograft vessels enhances allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by inhibiting an increase in CD161(+) regulatory T cells. == Introduction == Cell-mediated vascular rejection is usually a major cause of allograft loss in solid organ transplantation (13). Acute rejection in humans correlates with the frequency of memory T cells that directly recognize nonself MHC molecules displayed by graft cells (4). Human ECs display both class I and class II MHC molecules as well as costimulators effective in the activation of memory T cells and are an apparent target for alloreactive effector memory T cells of the host (5,6). This may result in a pattern of acute cell-mediated vascular rejection known as intimal arteritis that is characterized by sub-endothelial infiltration of mononuclear cells, EC injury (endothelialitis) and vigorous intimal expansion (7). Sub-endothelial T cells and macrophages are also found in a form of chronic vascular rejection, known as graft arteriosclerosis or allograft vasculopathy, characterized by a concentric intimal expansion by smooth muscle cells and inadequate compensatory outward remodeling with less overt evidence of graft cell injury (8). Both intimal arteritis and allograft vasculopathy are often resistant to available immunosuppressive therapies (7) and acute vascular rejection, even when reversed, may pre-dispose to the latter change (912). T cell infiltration and rejection of the graft arterial wall may be uncoupled from other manifestations of rejection in the graft parenchyma. Understanding the mechanism(s) involved in the host T cell response to graft arteries is crucial for development Alcaftadine of new treatments. Whereas target cell killing by cytolytic T cells is a hallmark of acute rejection, release of IFN by infiltrating T cells is Alcaftadine also characteristic and, in the absence of cytolysis, may underlie the development of graft arteriosclerosis (13). Importantly, human arteries transplanted into immunodeficient mouse hosts develop arteriosclerotic intimal expansion in response to human IFN in absence of Alcaftadine an immune response (14). Furthermore, antibody-mediated neutralization of IFN protects human artery grafts from rejection by adoptively transferred allogeneic human T cells in a humanized mouse model of intimal arteritis (15). Controlling IFN production by host T cells thus would seem to be a key strategy for protecting graft arteries from rejection. Activated CD4(+) T cells may be polarized to produce a specific subset of cytokines. Effector Alcaftadine CD4(+) T lymphocytes were initially classified as Th1 or Th2 cells, producing high amounts of IFN or mixtures of IL-4, IL-5 and IL-13, respectively (16). More recently a third subset of Th cells has been described, called Th17 cells, which primarily produce IL-17A, IL-17F and IL-22 (17). In the circulation of adult humans, these cells are exclusively contained within a populace of effector memory T cells that express CD161 (18), a type II transmembrane glycoprotein that had previously been described as a receptor expressed on natural killer cells (19). CD161 expression is usually controlled by the same transcription factor, RORT in mice or RORc in humans, that is associated with Th17 development (20). However, even though all IL-17-producing cells express CD161, not all CD161(+) T cells will differentiate into Th17 cells (18,20). Furthermore, most IL-17A-producing T cells isolated from human arteries also produce IFN (21), implying that not all IL-17-producing T cells are actually Th17 cells. A fourth group of CD4(+) T cells has been described that can suppress cytokine production by effector Th cells of various subsets. Such regulatory T cells are themselves heterogeneous. Natural T regulatory cells (n-Tregs) emerge directly from the thymus expressing high levels of forkhead box P3 (FoxP3) and Helios transcription factors and are characterized by high surface expression of CD25 and low expression of CD127 (20,2227). N-Tregs respond to self antigens and control autoimmunity (24,28,29). Other populations of regulatory T cells develop or convert from CD4(+) effector T cells and are specific for non-self antigens, including alloantigens (3034). These inducible T regulatory cells (i-Tregs) are Helios unfavorable (27) and may or may not express FoxP3 (35); i-Tregs are likely responsible for the control of allograft rejection in the process described as Rabbit Polyclonal to COX5A infectious tolerance (36,37). An i-Treg populace has recently been described that can control acute arterial rejection.