Role of T regulatory suppression in autoimmunity and can

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Abstract

It has recently become clear that a subset of T cells e.g. T regulatory (Treg) cells have feedback suppressive effects on immune responses. These Treg cells have been reported to suppress autoimmune responses and consequently, unfortunately, also reported to protect tumors from immune rejection. During this fiscal year, we showed that the immunosuppressive agent dexamethasone (DEX), which is used to treat autoimmune disease, and the lymphoproliferative cytokine Interleukin-2, each upregulated the number and function of Treg cells in mice. Furthermore, when administered together they had even greater effects in promoting immunosuppressive Treg cell activities. When administered together prior to an antigen (MOG) that induces experimental autoimmune encephalomyelitis (EAE), IL-2 plus DEX reduced the incidence and severity of EAE in susceptible mice. Thus, upregulation of Tregs can counteract induction of autoimmune reactions.Pertussis toxin (PTX) is coadministered as an adjuvant along with an appropriate autoantigen in Complete Freunds adjuvant (CFA) in order to induce EAE in susceptible mouse strains. This co-adjuvant effect of PTX has been ascribed to induction of increased permeability of the blood brain barrier. However, we observed that mice in the course of developing EAE experienced a decrease in the number of functional Treg cells. Independent evaluation of the different agents given to mice revealed that the PTX by itself rather than the CFA or antigen was responsible for the decrease in suppressive Treg cells. Obviously PTX has multiple biological effects of suppressing Treg cells in vivo and interfering with GiPCR signal transduction. In a separate study we observed that PTX also activated dendritic cell maturation in vitro and this required TLR4 expression and signal transduction. Thus, the adjuvant effects of PTX in addition to inhibiting Treg cells also involve activation of immunoenhancing TLR4 responses. Based on these observations the effects of PTX on inducing tumor immunity will be investigated. We plan to further pursue the identification of agents that influence Treg cell functions, since they can be used to modulate autoimmunity and tumor cell growth.