Abstract
Tissue homeostasis is critically dependent on the function of tissue-resident lymphocytes, including lipid-reactive invariant natural killer T (iNKT) cells. Yet, if and how the tissue environment shapes the antigen specificity of iNKT cells remains unknown. By analysing iNKT cells from lymphoid tissues of mice and humans we demonstrate that their T cell receptor (TCR) repertoire is highly diverse and is distinct for cells from various tissues resulting in differential lipid-antigen recognition. Within peripheral tissues iNKT cell recent thymic emigrants exhibit a different TCR repertoire than mature cells, suggesting that the iNKT population is shaped after arrival to the periphery. Consistent with this, iNKT cells from different organs show distinct basal activation, proliferation and clonal expansion. Moreover, the iNKT cell TCR repertoire changes following immunisation and is shaped by age and environmental changes. Thus, post-thymic modification of the TCR-repertoire underpins the distinct antigen specificity for iNKT cells in peripheral tissues.
Highlights
Most anatomical compartments, including mucosal surfaces and solid organs, host large populations of tissue-resident lymphocytes which are uniquely placed to provide local networks for immune surveillance and defence against infection (Fan and Rudensky, 2016)
By combining flow-cytometry analyses, lipid-loaded tetramers and RNA sequencing (RNAseq) experiments we demonstrate that the invariant natural killer T (iNKT) cell T cell receptor (TCR) repertoire is highly polyclonal and it is different for iNKT cells resident in various tissues resulting in differential lipid antigen recognition
Because iNKT cell subpopulations are present at different proportions in the various lymphoid organs we evaluated whether the changes in proliferation, basal activation and TCR repertoire could be due to different iNKT subsets present in those tissues
Summary
Most anatomical compartments, including mucosal surfaces and solid organs, host large populations of tissue-resident lymphocytes which are uniquely placed to provide local networks for immune surveillance and defence against infection (Fan and Rudensky, 2016). Beyond the common features shared by all iNKT cells (including their CD1-restriction and innate-like properties), cells found in discrete tissues have distinct phenotypes and functions that critically modulate the outcome of immunity (Crosby and Kronenberg, 2018) This suggests that unique tissuespecific factors (including local lipid antigens, cytokines and/or hormones) may shape the population of iNKT cells resident in those tissues, regulating local immune responses. INKT cells have been traditionally defined by the expression of an invariant TCR a-chain (Va14Ja18 in mice or Va24-Ja18 in humans) and their capacity to recognise the glycolipid antigen a-galactosylceramide (aGalCer) presented on CD1d Despite this prototypical TCR repertoire gene usage, in recent years it has become apparent that there are variations within the iNKT cell repertoire that impact the antigen recognition capacity and the functional outcomes during an immune response. Our data uncovers a novel mechanism of tissue-specific immunoregulation that underpins the antigen-specificity of iNKT cells in different sites
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