Siglec 5 - a novel checkpoint receptor in T cells

Abstract

Abstract Immune checkpoint molecules have become a major target for designing immunotherapies. Across fourteen malignancies, the FDA has approved six drugs targeting three different inhibitory checkpoint receptors. Even though TCR stimulation through MHC-peptide and CD28 co-stimulation are the major requirements for T cell activation, it is the engagement of checkpoint receptors that dictate the functional outcome of a particular T cell. Here, we describe a new candidate checkpoint receptor, Siglec 5, expressed on activated T cells. To date, Siglec 5 is defined as a self-associated molecular pattern receptor that exhibits an inhibitory response upon interaction with sialic acids, subsequently dampening immune system activation against self. Current literature shows that Siglec 5 is expressed mainly by myeloid cell, such as neutrophils and monocytes, and that T cells do not express any Siglecs, including Siglec 5. However, we found that Siglec 5 is a unique, late-activation marker of T cells, upregulated at 48 hours, with peak expression at 72 hours post-TCR stimulation. Similar to PD-1, Siglec 5 has an ITIM and a SWITCH domain, both well described for their inhibitory function. In this study, we sought to determine the function of Siglec 5 on T cell activation. We found that overexpression of Siglec 5 in T cells results in a significant inhibition of T cell activation measured by reporter NFAT and AP-1 activity. Mutagenesis studies show that both of the intracellular domains, ITIM and SWITCH, of Siglec 5 are required for mediating T cell inhibition. Together, these data demonstrate that Siglec 5 is a previously unknown immune checkpoint molecule found on T cells.