SAP-Dependent and -Independent Regulation of Innate T Cell Development Involving SLAMF Receptors.

Jaime De Calisto,Ninghai Wang,Cox Terhorst,Pablo Engel,Burcu Yigit,Guoxing Wang

doi:10.3389/fimmu.2014.00186

Abstract

Signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) plays an essential role in the immune system mediating the function of several members of the SLAM family (SLAMF) of receptors, whose expression is essential for T, NK, and B-cell responses. Additionally, the expression of SAP in double-positive thymocytes is mandatory for natural killer T (NKT) cells and, in mouse, for innate CD8+ T cell development. To date, only two members of the SLAMF of receptors, Slamf1 and Slamf6, have been shown to positively cooperate during NKT cell differentiation in mouse. However, it is less clear whether other members of this family may also participate in the development of these innate T cells. Here, we show that Slamf[1 + 6]−/− and Slamf[1 + 5 + 6]−/−B6 mice have ~70% reduction of NKT cells compared to wild-type B6 mice. Unexpectedly, the proportion of innate CD8+ T cells slightly increased in the Slamf[1 + 5 + 6]−/−, but not in the Slamf[1 + 6]−/− strain, suggesting that Slamf5 may function as a negative regulator of innate CD8+ T cell development. Accordingly, Slamf5−/− B6 mice showed an exclusive expansion of innate CD8+ T cells, but not NKT cells. Interestingly, the SAP-independent Slamf7−/− strain showed an expansion of both splenic innate CD8+ T cells and thymic NKT cells. On the other hand, and similar to what was recently shown in Slamf3−/− BALB/c mice, the proportions of thymic promyelocytic leukemia zinc finger (PLZFhi) NKT cells and innate CD8+ T cells significantly increased in the SAP-independent Slamf8−/− BALB/c strain. In summary, these results show that NKT and innate CD8+ T cell development can be regulated in a SAP-dependent and -independent fashion by SLAMF receptors, in which Slamf1, Slamf6, and Slamf8 affect development of NKT cells, and that Slamf5, Slamf7, and Slamf8 affect the development of innate CD8+ T cells.

Highlights

During mainstream T lymphocyte development, some of the key factors that drive the transition from double-positive (DP) CD4+CD8+ precursors to single positive (SP) T cells involve antigen specificity and TCR strength [1,2,3]
As previously reported [20, 22], we found that the homotypic SAPdependent receptors Slamf1, Slamf3, Slamf5, and Slamf6 are moderately to highly expressed by DP TCRβlow thymocytes
Thymic innate CD8+ T cells maintained the levels of Slamf1, Slamf4, and Slamf6 expression compared to DP TCRβlow thymocytes, but slightly upregulated Slamf2, Slamf3, and Slamf5 (Figure S1D in Supplementary Material)

Summary

Introduction

During mainstream T lymphocyte development, some of the key factors that drive the transition from double-positive (DP) CD4+CD8+ precursors to single positive (SP) T cells involve antigen specificity and TCR strength [1,2,3] During this process, thymic epithelial cells interact with DP cells to determine the fate of immature thymocytes by orchestrating positive and negative selection [4,5,6,7]. During development in the thymus, as well as in the effector phase in the periphery, NKT and innate CD8+ T cells, which have a restricted TCR repertoire, interact with different nonclassical MHC class I molecules [11,12,13,14]. This suggests that differential SLAMF receptor expression can positively or negatively influence innate T cell development

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