Abstract
Invariant Natural Killer T (iNKT) cells are a T cell subset expressing an invariant T Cell Receptor (TCR) that recognizes glycolipid antigens rather than peptides. The cells have both innate-like rapid cytokine release, and adaptive-like thymic positive selection. iNKT cell activation has been implicated in the pathogenesis of allergic asthma and inflammatory diseases, while reduced iNKT cell activation promotes infectious disease, cancer and certain autoimmune diseases such as Type 1 diabetes (T1D). Therapeutic means to reduce or deplete iNKT cells could treat inflammatory diseases, while approaches to promote their activation may have potential in certain infectious diseases, cancer or autoimmunity. Thus, we developed invariant TCR-specific monoclonal antibodies to better understand the role of iNKT cells in disease. We report here the first monoclonal antibodies specific for the mouse invariant TCR that by modifying the Fc construct can specifically deplete or activate iNKT cells in vivo in otherwise fully immuno-competent animals. We have used both the depleting and activating version of the antibody in the NOD model of T1D. As demonstrated previously using genetically iNKT cell deficient NOD mice, and in studies of glycolipid antigen activated iNKT cells in standard NOD mice, we found that antibody mediated depletion or activation of iNKT cells respectively accelerated and retarded T1D onset. In BALB/c mice, ovalbumin (OVA) mediated airway hyper-reactivity (AHR) was abrogated with iNKT cell depletion prior to OVA sensitization, confirming studies in knockout mice. Depletion of iNKT cells after sensitization had no effect on AHR in the conducting airways but did reduce AHR in the lung periphery. This result raises caution in the interpretation of studies that use animals that are genetically iNKT cell deficient from birth. These activating and depleting antibodies provide a novel tool to assess the therapeutic potential of iNKT cell manipulation.
Highlights
Invariant Natural Killer T cells have an invariant T Cell receptor (TCR), that in contrast to conventional T cells recognize glycolipid antigens that are presented on the MHC I like molecule CD1d. iNKT cells share surface markers and functional characteristics with both conventional T cells and natural killer (NK) cells [1,2]. iNKT cells represent a very small subset of the total T cell population in human and non-human peripheral blood
While iNKT cell activity has been implicated in the pathogenesis of asthma and inflammatory diseases such as sickle cell disease (SCD) [4,5,6,7,8,9,10], the pharmacologic activation of iNKT cells using glycolipid superagonist alpha-Galactosyl-ceramide has shown them to be protective in the NOD mouse model of autoimmune Type 1 diabetes (T1D) [11,12]
We demonstrate here for the first time monoclonal antibodies specific for the mouse invariant TCR
Summary
Invariant Natural Killer T (iNKT) cells have an invariant T Cell receptor (TCR), that in contrast to conventional T cells recognize glycolipid antigens that are presented on the MHC I like molecule CD1d. iNKT cells share surface markers and functional characteristics with both conventional T cells and natural killer (NK) cells [1,2]. iNKT cells represent a very small subset of the total T cell population in human and non-human peripheral blood. INKT cells represent a very small subset of the total T cell population in human and non-human peripheral blood In humans, their abundancy ranges from less than 0.01% of all T cells to higher than 1.0%, with the majority of individuals clustering at the lower end of the range. In inbred mice iNKT cells are still a rare population but in the higher range of 0.5%-2% with very little within-strain animal to animal variation [3]. Despite their low frequency iNKT cells have potent immune-regulatory functions as they are constitutively expressing high levels of a wide variety pro-inflammatory as well as immune-regulatory cytokines and chemokines that are rapidly released upon iTCR engagement [2]. To validate the function of the antibodies tested their efficacy in the NOD model of T1D and in a mouse model of allergic airway inflammation and airway hyperresponsiveness (AHR) [5] a model of allergic asthma [7]
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