EF Hand Domain Family Member D2 Is Required for T Cell Cytotoxicity

Abstract

Programmed cell death-1 (PD-1) is a major co-inhibitory receptor and a member of the immunological synapse (IS). To uncover proteins that regulate PD-1 recruitment to the IS, we searched for cytoskeleton-related proteins that also interact with PD-1 using affinity purification mass spectrometry. Among these proteins, EF Hand domain family member D2 (EFHD2), a calcium binding adaptor protein, was functionally and mechanistically analyzed for its contribution to PD-1 signaling. EFHD2 was required for PD-1 to inhibit cytokine secretion, proliferation and adhesion of human T cells. Interestingly, EFHD2 was also required for human T cell-mediated cytotoxicity and for mounting an anti-tumor immune response in a syngeneic murine tumor model. Mechanistically, EFHD2 contributed to IS stability, lytic vesicles trafficking, and granzyme B secretion. Altogether, EFHD2 is an important regulator of T cell cytotoxicity, and further studies should evaluate its role in T cell-mediated inflammation.

B Cell Speed and B-FDC Contacts in Germinal Centers Determine Plasma Cell Output via Swiprosin-1/EFhd2

“…Nevertheless, we conclude that the upregulation of EFhd2 in GC B cells stabilizes B cell/FDC contacts. In line with our finding, EFhd2 stabilizes the CD8 T cell synapse and supports PD-1-mediated T cell suppression in vitro (Peled et al, 2018). Based on our previous B-cell-intrinsic results (Brachs et al, 2014), we used total EFhd2KO mice, and this could arguably lead to increased T cell help in GCs.…”

Comparative Genomics Reveals 13 Different Isoforms of Mytimycins (A-M) in Mytilus galloprovincialis

“…While Ca 2+ is crucial in the cardiac excitation-contraction coupling [ 24 , 25 ], it also participates in many other important biological processes, including immune functions. Proteins containing an EF-hand domain are thought to be an important regulator of T cell cytotoxicity [ 26 ]; this domain is also found in calmodulin-like 6 (CALML6), where it suppresses antiviral response by preventing the translocation of IRF3 (interferon regulatory factor (3)) into the nucleus and inhibiting the IFN pathway [ 27 ]. While the functional meaning of the EF-hand domain in the mytimycin precursor peptides remains unknown, it is tempting to speculate that it could be involved in innate immune response to pathogens, activating pattern recognition receptors and mediating inflammation processes [ 28 ].…”

Innate immune activation restricts priming and protective efficacy of the radiation-attenuated PfSPZ malaria vaccine

“…SEC62 encodes a translocon component that is critical for maintaining ER homeostasis during stress recovery (Fumagalli et al, 2016). A single module positively correlated with protection and was led by the hub-gene EFHD2, which encodes a calcium-binding protein that was shown to positively regulate the B-cell-receptor induced intracellular calcium response (Kroczek et al, 2010) and is required for human T-cell mediated cytotoxicity (Peled et al, 2018) (Figure 2A). Network graphs of nodal correlations revealed that modules negatively correlated with protection were tightly linked to each other and only weakly linked to the protectionassociated EFHD2 module (Figure 2B).…”