Phenotypical and functional characterization of murine iNKT1, 2, and 17 cells

Invariant natural killer T (iNKT) cells represent a subpopulation of T cells performing specialized functions. iNKT cells come into existence in thymus and are derived from double positive thymocytes. Cells recruited into the iNKT pathway express a highly restricted set of alpha/beta TCR coining the name invariant. These TCR are capable to recognize non-peptide components such as glycolipids that are presented to iNKT cells in the context of CD1d, a polypeptide related to MHC class I.
Recently, there was a fundamental reorientation in our understanding of iNKT cell differentiation and function. In contrast to the classical hypothesis defining iNKT subsets by developmental intermediates, a new concept emerged called lineage diversity model. This new model gained quick acceptance in the literature due to its capability to correlate a simple definition of iNKT subsets with functional aspects. Thus, expression of a few key transcription factors or surface markers suffices to clearly define three iNKT subpopulations possessing distinct cytokine expression profiles. Indeed, iNKT cells resemble effector CD4 T cells and the three iNKT subsets defined according to the lineage diversity model predominantly produce either IFN-gamma, or IL-4 or IL-17 wherefore they are named iNKT1, iNKT2, and iNKT17 cells, respectively, in analogy to the well-established T helper cell paradigm. Nevertheless, mainly due to its novelty, the iNKT1/2/17-concept lacks a broad experimental support when referring to iNKT cells of the periphery. iNKT cells can be found in virtually all peripheral lymphoid as well as non-lymphoid organs such as liver, lung and intestine and it is conceivable that organ-specific micro-milieus imprint functional peculiarities onto the endemic iNKT populations. Therefore, we plan to decipher such features by a comprehensive comparative study of peripheral iNKT subpopulations isolated from several organs. To capture differences, we will perform comparative transcriptome analyses. This will be complemented by studies of the migratory and differentiation potential of peripheral iNKT subsets. Their functional aspects will be further elucidated in several mouse models of colitis and asthma. It is also intended to focus on the consequences of distinct gene deficiencies on the function and/or differentiation of iNKT cells. In the course of our earlier work, we already identified several candidate genes and would expect that the experiments proposed here will unravel additional genes that influence iNKT cell biology.