IRCM Researchers

By discovering that the CD4 and CD8 T cell co-receptors associate with the protein tyrosine kinase Lck, Dr. Veillette was one of the founders of the field of immune cell activation over 30 years ago. Since then, Dr. Veillette and his lab continued to make important discoveries in this field and to provide fundamental insights into immunological mechanisms in health and disease.

1. Discovery that the CD4 and CD8 T cell surface antigens are associated with the Src-related protein tyrosine kinase Lck (Cell, 1988), and that Lck is implicated for the initiation of T-cell receptormediated T cell activation (Nature, 1989; Nature, 1991). A similar role in T cell receptor signaling was ascribed to Fyn, another Src-related enzyme found in T cells (J. Exp. Med., 1991).

2. Discovery that the protein tyrosine kinase Csk is a crucial component of the inhibitory machinery suppressing T cell activation, as a result of its capacity to inactivate Src family kinases (Nature, 1993). This function requires the association of Csk with PTPN22/Lyp/PEP, a protein tyrosine phosphatase also implicated in the inhibition of T cell activation (The EMBO Journal, 1996; J. Exp. Med., 1999). It is of note that polymorphisms in PTPN22/Lyp/PEP that interfere with the ability of the phosphatase to associate with Csk are strongly linked to susceptibility to auto-immune diseases in humans. The activity of Csk also requires the interaction with the adaptor PAG in activated T cells (Cell Rep., 2016).

3. Discovery that the adaptor molecule SAP, which is mutated in X-linked lymphoproliferative (XLP) disease in humans, plays a critical role in immune regulation by promoting, through a unique and novel signaling mechanism, the recruitment of Src-related protein tyrosine kinase Fyn to the SLAM family of immune cell-specific receptors (Nature Immunology, 2001; Nature Cell Biology, 2003; Immunity, 2004). Discovery that SAP family adaptors and SLAM family receptors play key role in the capacity of natural killer cells to kill abnormal cells and that SLAM family receptors control iNKT cell development and the germinal centre reaction (Nature Immunology, 2009; Immunity, 2012; Nature Immunology, 2016; Nature Immunology, 2019; J. Exp. Med., 2021).

4. Discovery that the SLAM family receptor SLAMF7 and the integrin CD11b/Mac-1 are critical for the ability of macrophages to engulf and destroy cancer cells in response to SIRPα-CD47 blockade (Nature, 2017). And subsequent discovery that, in inflammatory macrophages, the unconventional prophagocytic integrins CD11a/CD18 and CD11c/CD18 bypass the requirement of SLAMF7 and CD11b for phagocytosis of tumor cells in response to SIRPα-CD47 blockade (2021, in revision).