Cutting Edge: The Signals for the Generation


CD8 T cell memory critically contributes to long-term immunity. Both low-and high-affinity TCR signals are able to support the differentiation of memory CD8 T cells. However, it is unclear whether the requirements for memory development change when TCR signal strength is altered. To gain further insight into this question, we used a TCRb transmembrane domain mutant model that is defective in the generation of memory in response to high-affinity ligands. Surprisingly , lowering TCR signal strength, by stimulation with low-affinity ligands, resulted in normal memory development. Restoration of memory correlated with recovery of TCR-dependent NF-kB signaling. Thus, these data provide novel evidence that the requirements for memory are qualitatively different depending on TCR signal strength. M emory CD8 T cells provide protective immunity against intracellular pathogens and tumors. It has been assumed that high-affinity TCR ligands are required for naive CD8 T cells to acquire effector function and differentiate into long-lived memory T cells. However, there is compelling evidence that low-affinity TCR ligands support memory development (1–4). In the context of infection, T cells responding to low-affinity TCR ligands are able to differentiate into functional memory T cells (5). Furthermore, in lymphopenic conditions, T cells homeostatically proliferate (HP) and develop into memory cells in response to self-peptide–MHC complexes (low affinity), high levels of ho-meostatic cytokines, and low levels of inflammation (6–8). These HP memory T cells are similar to Ag-experienced (true) memory cells at clearing pathogens upon infection and generating secondary memory (9). Curiously, T cells differentiating into memory under lymphopenic conditions exhibit an expression profile that is comparable with Ag-experienced cells. However, it remains unclear whether the biochemical mechanisms required to induce the memory program are the same for T cells stimulated by high-versus low-affinity TCR ligands. Indeed, the TCR is able to differentially signal depending on the ligand it recognizes (10–12). In line with this, recent data suggest that the TCR can selectively regulate the transduction of signals that drive T cell memory (2, 13, 14). We have previously shown that CD8 T cells bearing a point mutation in the TCRb transmembrane domain (bTMDmut or MUT) acquire effector function but are uniquely defective in the development of memory in response to high-affinity TCR ligands (13). In this article, we show unexpectedly that lowering TCR affinity leads to a recovery in memory programming in MUT T cells. This process was dependent on NF-kB signaling, which was efficiently triggered by …

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@inproceedings{Jameson2013CuttingET, title={Cutting Edge: The Signals for the Generation}, author={Stephen C. Jameson and Emma Teixeiro and Karin Knudson and Sara E. Hamilton and Mark A Daniels}, year={2013} }