Cellular and Molecular Mechanisms of Immunoregulation In Vivo
Protective immunity requires a balance between pro-and anti-inflammatory responses. Absence of regulation of pro-inflammatory responses can lead to lethal tissue damage and pathologies such allergy and autoimmune disease. However, aberrant anti-inflammatory responses allow for uncontrolled pathogen replication, and progression of malignancies such as cancer. Thus, a balance between pro- and anti-inflammatory responses confers protection to the host. Redundant and non-redundant mechanisms of immunoregulation exist that establish the balance between inflammatory responses to maintain homeostasis. Also, these immunoregulatory mechanisms act at different layers of the immune response to maintain homeostasis including: epithelial barriers, innate responses, and adaptive responses. Programed death-1 (PD-1) is an inhibitory co-stimulatory molecule originally described to promote exhaustion or inhibit the function of effector T cells. PD-1 deficiency is associated with tissue specific autoimmune disease while overexpression leads to immunological anergy. In this dissertation we report a previously unknown regulatory role of PD-1 that leads to inhibition of protective immunity. PD-1 deficiency promotes the production of the immunosuppressive cytokine interleukin-10 (IL-10). Enhanced IL-10 production inhibits the production of protective type-1 cytokines that control parasite replication and render PD-1-/- mice susceptible to the protozoan parasite Toxoplasma gondii. Thus, we describe a new counter-regulatory activity of PD-1. Further, in this dissertation we report on the immunoregulatory effects of the epithelial repair protein trefoil factor 2 (TFF2). TFF2 is a well-established regulator of epithelial reconstitution. Our data demonstrates that TFF2 negatively regulates type-1 immune responses during steady state conditions. Also, following oral inoculation with T. gondii, protective immune responses are increased in TFF2-/- mice. The elevated type-1 responses correlate with low levels of parasite replication and reduced immunopathology compared to control animals. TFF2 effects are both intrinsic and extrinsic, as TFF2-/- macrophages and dendritic cells (DCs) were hyper-responsive to Toll-like receptor stimulation; and rTFF2 was able to suppress inflammatory cytokine production from wild-type DCs. Hence, our data demonstrate that TFF2 is a negative regulator of type-1 immune responses. Lipoxin A4 (LXA4) and L-kynurenine are counter-regulatory molecules produced in response to arachidonic acid or tryptophan metabolism. However, the intracellular counter-regulatory signaling pathways that are triggered in response to their stimulation of cells are unclear. We report that both molecules inhibit the pro-inflammatory activities of DCs by inducing the nuclear translocation of the aryl-hydrocarbon receptor (AhR). This response promotes expression of the suppressor of cytokine signaling 2 (SOCS2), which causes proteasome-dependent degradation of TRAF6. Therefore, our report provides insight into the intracellular signaling pathways triggered to prevent aberrant inflammation and tissue damage. Taken together, our data demonstrate novel mechanisms of immunoregulation that act at the epithelial barrier, on APCs, and on T cells to provide protection from immunopathological type-1 immunity by establishing balance between pro-and anti-inflammatory responses.
Immunology, PD1, IL10, TFF2, Lkynurenine, lipoxin, counter regulation
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