Research highlights

Lymphocyte development: SLAM dunk for innate T cells

Nature Reviews Immunology 8, 1 (January 2008) | doi:10.1038/nri2243

Different innate-like T-cell subsets were investigated in each report. Griewank et al. studied natural killer T (NKT) cells, which are selected by CD1d ligands that are expressed by cortical thymocytes. Li et al. studied a thymocyte-selected CD4⁺ T-cell subset that has been observed in mice with forced expression of MHC class II molecules by thymocytes. Horai et al. focused on a population of innate-like CD8⁺ T cells that expands when the TEC family kinase ITK (interleukin-2-inducible T-cell kinase) is lacking.

Using various bone-marrow chimaera approaches, Griewank et al. showed that NKT-cell development requires signalling that is initiated by homotypic interactions with thymocyte-expressed SLAM receptors, in particular SLAMF1–SLAMF1 and SLAMF6–SLAMF6 interactions. Accordingly, and in keeping with previous studies, the absence of the SLAM signalling components SAP (SLAM-associated protein) and FYN caused an arrest in NKT-cell development. Importantly, interaction between the SLAM receptors on the selecting thymocyte and on the NKT-cell precursor was needed at the same time as T-cell receptor (TCR) engagement with CD1d molecules expressed by the same thymocyte.

Li et al. also observed a central requirement for SAP and FYN in the development of thymocyte-selected CD4⁺ T cells. Protein kinase C (PKC), which is activated by FYN to mediate TCR-induced nuclear-factor-B activation, also seems to be important. Similar to NKT cells, when these thymocyte-selected CD4⁺ T cells leave the thymus they produce both T-helper-1-type and T-helper-2-type cytokines immediately after stimulation without the need for further differentiation; T-bet and SAP were shown to be crucial for the optimal production of these cytokines, respectively.

Extending their previous observations, Horai et al. showed that when ITK-deficient bone-marrow cells are transferred into mice that lack MHC class I molecules, CD8⁺ T cells are selected by MHC class I molecules on the transferred haematopoietic cells and this results in CD8⁺ T cells with innate-like properties. This selection is now shown to be SAP dependent, and acquisition of their innate-like properties is shown to require the co-receptor CD28. Notably, when ITK-deficient thymocytes were forced to be selected on the thymic stroma, the induction of cells with innate-like properties was much less efficient, highlighting a key role for haematopoietic-cell-mediated selection. Given that ITK seems to be required specifically for efficient differentiation of conventional CD8⁺ T cells, the authors suggest that SAP and ITK may reciprocally regulate the selection of innate-like CD8⁺ T cells on haematopoietic cells.

Together, these studies help to define pathways of T-cell selection on haematopoietic cells and indicate an important role for SLAM receptor signalling in these alternative pathways of T-cell development.

Author: Lucy Bird