Abstract
The signaling lymphocytic activation molecule (SLAM) family is comprised of nine distinct receptors that are expressed exclusively on hematopoietic cells. Most of these transmembrane receptors are homotypic by nature and downstream signaling occurs when cells that express the same SLAM receptor interact. Previous studies have determined that anti-SLAMF6 antibodies can have a therapeutic effect in autoimmunity and cancer. However, little is known about the role of SLAMF6 in the adaptive immune responses and in order to utilize SLAMF6 interventional approaches, a better understanding of the biology of this receptor in T cell is warranted. Accordingly, the objective of our study was to investigate both functionally and structurally the role of SLAMF6 in T cell receptor (TCR) mediated responses. Biochemical and genetic experiments revealed that SLAMF6 was required for productive TCR downstream signaling. Interestingly, SLAMF6 ectodomain was required for its function, but not for its recruitment to the immunological synapse. Flow-cytometry analysis demonstrated that tyrosine 308 of the tail of SLAMF6 was crucial for its ability to enhance T cell function. Imaging studies revealed that SLAMF6 clustering, specifically with the TCR, resulted in dramatic increase in downstream signaling. Mechanistically, we showed that SLAMF6 enhanced T cell function by increasing T cell adhesiveness through activation of the small GTPase Rap1. Taken together SLAMF6 is an important regulator of T cell activation where both its ectodomain and its endodomain contribute differentially to T cell functions. Additional studies are underway to better evaluate the role of anti-SLAMF6 approaches in specific human diseases.
Highlights
The T cell receptor (TCR) is a complex of proteins found on the surface of T cells and is utilized to recognize antigens that are presented in the context of major histocompatibility complex (MHC) class I or class II molecules located on the surface of antigen presenting cells (APC) [1]
When we engaged SLAMF6 and the TCR with antibodies, a clear increase in TCR activity can be seen over controls that did not have antibody engaged SLAMF6
When SLAMF6 was knocked down or knocked out, we have shown a decrease in TCR activity post TCR engagement
Summary
The T cell receptor (TCR) is a complex of proteins found on the surface of T cells and is utilized to recognize antigens that are presented in the context of major histocompatibility complex (MHC) class I or class II molecules located on the surface of antigen presenting cells (APC) [1]. Along with the TCR-MHC complex, further signals in the form of co-receptors are required for proper T cell activation. For cytotoxic T cells the additional MHC class I ligating. In the case of helper and regulatory T cells the co-receptor is CD4 which ligates MHC class II. In addition to TCR specific co-receptors, there are other co-receptors that are critical for T cell activation which do not associate directly with the MHC. Such coreceptors include CD28, CD40L and CD2. In the instance of CD28 and CD40L, clustering in the immunological synapse (IS), the interface between T cells and APC, is a critical aspect of their function [4,5,6]
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