Molecular and biochemical requirements for inducing CD8⁺ T cell-mediated EBV-specific immunity. The scheme outlines the key cell surface receptor–induced signaling pathways required for generating CD8⁺ T-cell–mediated immunity against EBV, and how specific inborn errors of immunity (SH12D1A [SAP], MAGT1, ITK, CD27, CD70, TNFRSF9 [4-1BB], RASGRP1, and CTPS1; depicted in red) can compromise these processes. (A) Initial interactions between EBV-infected or antigen-presenting B cells and CD8⁺ T cells involve CD27/CD70, 4-1BB/4-1BBL, and major histocompatibility complex (MHC) class I/TCR. Signals elicited downstream of these receptors, requiring MAGT1, ITK, and RasGRP1, induce DNA synthesis via induction and activation of CTPS1 and subsequent proliferation of EBV-specific CD8⁺ T cells. Signals via CD27/CD70 and MAGT1 contribute to inducing or maintaining expression of activating receptors such as 2B4 and NKG2D. (B) Following expansion of EBV-specific CD8⁺ T cells, engagement of the activating SLAM family receptors 2B4 and NTB-A (via SAP) and the glycoprotein NKG2D by their ligands highly expressed on EBV-infected B cells induces cytolytic effector function, resulting in CD8⁺ T-cell–mediated killing of EBV⁺ target B cells.