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

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.

Slamf6 negatively regulates autoimmunity

“…It has been shown that Slamf1 and Slamf6 synergistically regulate NK T cell development [20, 30] This prompted us to evaluate whether combined deletion of Slamf[1+6] or Slamf[1+5+6] in CD4 + T cells can further influence GC formation and autoantibody production in bm12 recipients. Surprisingly, transfer of Slamf[1+6] −/− or Slamf[1+5+6] −/− CD4 + T cells did not increase numbers of splenocytes [WT: 80 ± 6×10 6 ; Slamf6 −/− 127 ± 12×10 6 ; Slamf[1+6] −/− 88± 4×10 6 ; Slamf[1+5+6] −/− 58 ± 5×10 6 ] in recipient bm12 mice, and resulted in significantly lower serum levels of anti-dsDNA, anti-ssDNA and anti-chromatin antibodies compared to that after the transfer of Slamf6 −/− CD4 + T cells (Fig.…”

“…Slamf5 −/− , Slamf6 −/− , Slamf[1+6] −/− and Slamf[1+5+6+] −/− mice were generated from C57BL/6 ES cells [17, 20, 21]. Slamf1 −/− [129xB6] was backcrossed ten times with B6 [22].…”

Clonal expansion of CD4+ cytotoxic T lymphocytes in patients with IgG4-related disease

“…Members of the SLAM family can be involved in both homotypic as well as heterotypic interactions 57, 58 . Given the presence of immune-receptor tyrosine based switch motifs (ITSMs) in its cytoplasmic tail, SLAMF7 can lead to activating or inhibitory signaling within the cell, depending on its association with a SLAM associated protein (SAP) family adaptor called EAT2.…”

“…Next-generation sequencing analysis of the TCR Vβ repertoire was undertaken using the ImmunoSeq® platform at Adaptive Biotechnologies Inc. at the “survey” level of sequencing depth, that is designed to target an output of 200,000 assembled output sequences after preprocessing filters 57, 58 . Briefly, genomic DNA was isolated from flow-sorted CD4 + T cell subsets (T EM , CD4 + SLAMF7 + CTLs and GATA-3+ T H 2 cells) from individual IgG4-RD subjects.…”

Development of invariant natural killer T cells

“…For example, the Slamf8-deficient mice have normal iNKT cell numbers but with an enlarged PLZF hi iNKT2 compartment [64]. Because the Slamf8 molecules signal independently of SAP and Slamf8-encoding mRNA is expressed in dendritic cells and fibroblasts in the thymus but not DP thymocytes, it is likely that Slamf8 functions differently than the other Slam-family molecules in affecting iNKT cell development [30,64,65,66]. Instead, these results suggest that DC cells or fibroblasts might provide external signals, which are affected by the absence of Slamf8, to developing iNKT cells.…”