Abstract
Invariant NKT (iNKT) cells are critical to the maintenance of tolerance toward alloantigens encountered during postnatal life pointing to the existence of a process for self-education. However, the impact of developmentally encountered alloantigens in shaping the phenotype and function of iNKT cells has not been described. To better understand this process, the current report examined naïve iNKT cells as they matured in an allogeneic environment. Following the prenatal transfer of fetal hematopoietic cells between age-matched allogeneic murine fetuses, cell-extrinsic signals appeared to dictate allospecific patterns of Ly49 receptor expression and lineage diversity in developing iNKT cells. Regulation for this process arose from cells of hematopoietic origin requiring only rare exposure to facilitate broad changes in developing iNKT cells. These findings highlight surprisingly asymmetric allospecific alterations in iNKT cells as they develop and mature in an allogeneic environment and establish a new paradigm for study of the self-education of iNKT cells.
Highlights
Invariant natural killer T cells have been shown to mediate immune responsiveness or tolerance in alternate settings[1]
Chimerism levels were approximately 2–15% in most tissues tested with the exception of thymic chimerism which was naturally low (Supplemental Fig. 1.) Invariant NKT (iNKT) cells were identified by TCR-βexpression and binding to CD1d-tetramers loaded with PBS57 glycolipid (Fig. 1b)
Given the invariant nature of TCR usage, the tolerogenic changes occurring in iNKT cells are likely limited to variations in inhibitory Ly49 receptor expression and iNKT cell lineage diversity
Summary
Invariant natural killer T cells (iNKT) have been shown to mediate immune responsiveness or tolerance in alternate settings[1]. Proposed pathways for self-recognition or alloreactivity of iNKT cells in mice include diversity of lipid-antigen recognition through the invariant TCR, inhibitory Ly49 (iLy49) interaction with class I ligands, and variation in iNKT lineage repertoire. Strain-specific MHC class I alleles provide a pathway for allorecognition by Ly49 receptors expressed by iNKT cells. Forced expression of the Ly49D receptor by immature thymocytes inhibits CD1d-restricted T cell development in a ligand-dependent manner indicating that activating Ly49 receptor signaling is incompatible with iNKT cell development[15,16]. For H-2Dd MHC class I antigen rescues iNKT cell development in the same model suggesting functionality of inhibitory Ly49 signaling in iNKT development[15,16]. Self-tolerance through differential responsiveness in various strains of mice may arise as iNKT cells mature into distinct lineages during development. A role for environmentally-derived signals in guiding fate decisions made by developing iNKT cells has not been well-studied
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