The ID of memory CD8⁺ T cells

Two recent studies published in Nature Immunology describe the differential expression of the transcriptional regulator ID3 in short-lived effector and long-lived memory CD8⁺ T cell subsets and its role in memory CD8⁺ T cell generation. Yang et al. identified two distinct CD8⁺ T cell populations (ID3^low and ID3^hi) in infected mice. ID3 expression preceded the expression of long-lived memory markers, and ID3^hiCD8⁺ T cells shared the phenotype and cytokine profile of long-lived memory T cells. Moreover, ID3^hiCD8⁺ T cells generated long-lived memory cells following their transfer into infected hosts. Ji et al. observed that the transcriptional repressor BLIMP1 (also known as PRDM1) — which is expressed in short-lived effector CD8⁺ T cells — downregulates ID3 expression. Both groups showed that ID3 is required for the generation of long-lived memory T cells because it promotes T cell survival, and this may be linked to ID3-dependent expression of genes involved in DNA repair (Ji et al.). Although both groups reported that ID3 does not influence the expression of ID2, Yang et al. found that loss of ID2 expression results in ID3 upregulation. Interleukin-2 (IL-2), IL-12 and IL-21 were shown to upregulate ID2 and downregulate ID3 expression, suggesting that the balance between ID2 and ID3 regulates memory CD8⁺ T cell generation in response to cytokines.