Session Type: Abstract Submissions (ACR)
Autoreactive invariant Natural Killer T (iNKT) cells have been implicated in several rheumatic diseases, including Systemic lupus erythematosus and Rheumatoid arthritis. iNKT cells are a unique subgroup of lymphocytes that recognize glycolipids presented by CD1d, and that express an invariant T cell Ag receptor (TCR) a chain. As a result of activation, iNKT cells secrete copious amount of cytokines, including IFNγ, IL-4, IL-17 and IL-21 and they mediate immune responses in various pathological conditions. Although several potential lipid self-antigens for iNKT cell development and activation have been identified, the mechanism by which iNKT cells react to CD1d-self-antigen is not understood yet. Our discoveries therefore will help identify novel drug targets for potential translational intervention in patients with SLE, RA and other autoimmune diseases in which abnormal activation of iNKT cells is observed.
In detecting autoreactivity, instead of iNKT cell hybridomas that have many limitations, we will use primary cultured mouse iNKT cells. Sorted as αGalCer-CD1d tetramers+ TCRb+, iNKT cells grow exponentially in vitro, and can be transduced by retroviruses in order to modulate differential expressions of important regulators. Microarray was carried out to identify new regulators of iNKT cell autoreactivity.
Our data show that the cultured iNKT cells have a greatly increased sensitivity to CD1d-lipid complexes derived from multiple sources, including soluble CD1d molecules produced in insect or mammalian cells, CD1d transfected cultured cells, and bone marrow-derived DCs. APCs that express a tail-deleted form of CD1d have a strongly diminished ability to stimulate the iNKT cell lines, indicating that the lines, like their primary cell counterparts in vivo, recognize auto-Ags loaded onto CD1d in endo/lysosomal compartments. Our results show that the iNKT cell lines preferentially respond to the auto Ags described previously when compared to the closely related homologs, despite their very different structures. Microarrays comparing the expression profiles of cultured and freshly isolated iNKT cells identifies SHP1/PTPN6, a tyrosine phosphatase that regulates TCR signaling, is down regulated in the iNKT cell lines. Reconstitution of the lines with the wild type but not the catalytically inactive SHP1 decreases the auto reactivity of the iNKT cell lines.
We hypothesize that iNKT cell TCR is intrinsically autoreactive, and instead of requiring a special autoantigens, many autologous Ags are capable of stimulating iNKT cells. The threshold of activation for iNKT cells are controlled during development and immune responses through key regulators, so that in the situation when this threshold is lowered, iNKT cells are activated by common lipid antigens that are present in the DP thymocytes or APCs. In the present study, taking advantage of a new system, we show the autoreactivity of polyclonal iNKT cells and we discover the protein tyrosine phosphatase SHP-1 (Ptpn6) is a critical regulator of the activation threshold of iNKT cells.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/shp-1-regulates-the-activation-threshold-of-inkt-cells/