T cell development in mice expressing CD1d directed by a classical MHC class II promoter.

Claire Forestier,Datsen Wei,Se-Ho Park,Albert Bendelac,Luc Teyton,Kamel Benlagha

doi:10.4049/jimmunol.171.8.4096

Claire Forestier, Datsen Wei + Show 4 more

Open Access

https://doi.org/10.4049/jimmunol.171.8.4096

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Abstract

CD1d and nonclassical MHC molecules differ markedly from classical MHC ligands in their ability to promote the selection and differentiation of developing T cells. Whereas classical MHC-restricted T cells have a predominantly naive phenotype and a broad TCR repertoire, most other T cells have a memory and/or NKT phenotype with a restricted repertoire. Because the nonclassical ligands selecting these memory-type cells are expressed by bone marrow-derived cells, it has been suggested that the development of large repertoires of naive-type cells was dependent on the classical MHC expression pattern in the thymus cortex, high on epithelial cells and low on cortical thymocytes. We redirected CD1d expression using the classical MHC II Ealpha promoter. pEalpha-CD1d mice lacked memory-type NKT cells, but, surprisingly, they did not acquire the reciprocal ability to select a diverse population of naive CD1d-restricted cells. These findings suggest that, whereas the development of NKT cells is dependent on the pattern of CD1d expression, the absence of a broad, naive CD1d-restricted T cell repertoire may reflect intrinsic limitations of the pool of TCR genes or lipid Ags.

Highlights

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Splenocytes and bone-marrow derived mature DCs from wild-type and pE␣-CD1d mice were pulsed with a range of concentrations of ␣GalCer, the exogenous glycolipid ligand recognized by NKT cells expressing the canonical V␣14-J␣18/V␤8 TCR, and cultured with the V␣14-J␣18/V␤8 DN32D3 hybridoma
By transgenically redirecting CD1d expression with the MHC class II E␣ promoter in CD1d KO mice, we have tested the hypothesis that the marked differences in thymic expression patterns between CD1d and MHC molecules were responsible for the corresponding differences in T cell repertoires

Summary

Abbreviations used in this paper

DN, double negative; ␣GalCer, ␣-galactosylceramide; KO, knockout. CD25ϩCD4ϩ cells, because the former largely dominate the CD1d-restricted T cell repertoire, whereas the latter represent Ͻ5% of the MHC class II-restricted CD4 population. Autoreactivity has only been demonstrated in the case of MR1-restricted cells, the memory phenotype of all of these T cells restricted by nonclassical MHC-like molecules again correlates with ligand expression on bone marrow-derived cells [13,14,15,16] These new findings suggest the intriguing hypothesis that selection by bone marrow-derived cells might ignore thymocytes engaged in low avidity or nonagonist interactions and only rescue those recognizing ligands with higher avidity or agonist properties [17]. These results suggest that NKT cell development requires tissue-specific, cognate interactions with cortical thymocytes rather than with epithelial cells They demonstrate that the intriguing absence of a significant population of naive-type CD1d-restricted T cells in mice is not a mere consequence of the unique pattern of CD1d expression in the thymus, but may instead reflect intrinsic limitations of the CD1d Ag presentation system, such as a reduced diversity of lipid Ags or of their corresponding TCR repertoire

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