The making of NKT cells

Abstract

Natural killer T cells acquire their unique phenotype and characteristics during development in the thymus. Evidence suggests that the transcription factor PLZF has a unique function in the development of these cells and their acquisition of ‘innate-like’ characteristics.

Figure 1. Schematic view of iNKT cell development

Natural Killer T cells arise in the thymus from uncommitted double negative (DN) precursors. The cells progress to the double-positive CD4⁺ CD8⁺ stage (DP) where they randomly rearrange the TCR. Thymocytes that express a TCR that interacts with CD1d bound to self-glycolipid, expressed by other DP thymocytes, enter the iNKT lineage. Homotypic interactions between SLAM and Ly108 molecules, also expressed at the surface of DP thymocytes, are required for progression into the iNKT cell lineage. After selection, iNKT-cell precursors undergo a series of differentiation steps characterized by the sequential expression of several cell surface markers (HSA, CD44 and NK1.1), as depicted. The earliest iNKT cell precursor found in the thymus expresses the highest level of PLZF. PLZF expression level then decreases as the cell progress further in the differentiation pathway. At least four distinct immature iNKT cell populations have been identified in the thymus. Most iNKT cells that emigrate from the thymus do so as immature (CD44^high, NK1.1⁻) and continue their final maturation in the periphery. This final maturation step is controlled by the transcription factor T-bet, whose expression level increases as a function of iNKT cell development. Some mature iNKT cells also migrate to the periphery but many remain as long-term resident of the thymus. In absence of PLZF, the cells fail to fully mature and preferentially accumulate in the lymph nodes instead of the spleen and the liver where wildtype iNKT cells usually reside.