Eomes broadens the scope of CD8 T-cell memory by inhibiting apoptosis in cells of low affinity

Abstract

The memory CD8 T-cell pool must select for clones that bind immunodominant epitopes with high affinity to efficiently counter reinfection. At the same time, it must retain a level of clonal diversity to allow recognition of pathogens with mutated epitopes. How the level of diversity within the memory pool is controlled is unclear, especially in the context of a selective drive for antigen affinity. We find that preservation of clones that bind the activating antigen with low affinity depends on expression of the transcription factor Eomes in the first days after antigen encounter. Eomes is induced at low activating signal strength and directly drives transcription of the prosurvival protein Bcl-2. At higher signal intensity, T-bet is induced which suppresses Bcl-2 and causes a relative survival advantage for cells of low affinity. Clones activated with high-affinity antigen form memory largely independent of Eomes and have a proliferative advantage over clones that bind the same antigen with low affinity. This causes high-affinity clones to prevail in the memory pool, despite their relative survival deficit. Genetic or therapeutic targeting of the Eomes/Bcl-2 axis reduces the clonal diversity of the memory pool, which diminishes its ability to respond to pathogens carrying mutations in immunodominant epitopes. Thus, we demonstrate on a molecular level how sufficient diversity of the memory pool is established in an environment of affinity-based selection.

Staggered starts in the race to T cell activation

“…Moreover, extensive work using APLs to stimulate naïve CD8 + T cells in multiple murine TCR transgenic systems showed that, starting from approximately 1 day after activation, T cells express IRF4 in a graded manner, reflecting stimulation strength [55][56][57][58]. As IRF4 can enhance effector differentiation [57,58], this suggests that subtle tuning of gene expression during the early days of naïve T cell activation might alter differentiation outcomes, as has been observed in in vivo models for both CD4 + and CD8 + T cells [47,[67][68][69][70][71][72]. Similarly, experiments stimulating murine CD4 + T cells with varying antigen doses found that, after 24 h, stimulation strength correlated with the expression of IL-12Rβ2, which facilitates Th1 polarization in response to IL-12 signaling [72].…”

Stem cell-like memory T cells: The generation and application

“…By regulating different AKT protein isoforms with different PIP3 levels, diversified downstream signaling pathways were activated and led to alternative cell fate 65 . When the cumulative signal intensity is appropriate, Tscm can be maximally induced 66 . The ratio of PI(4,5)P2 and PIP3 has been demonstrated to be a quantitative measurement for TCR signal strength.…”

Signals for antigen-independent differentiation of memory CD8+ T cells

“…Interestingly, this induction is stronger under submaximal TCR stimulation [ 62 ]. Also, in vivo submaximal TCR affinity results in the highest EOMES upregulation and drives central memory formation [ 76 ]. Besides IL-4, type 1 interferons (IFNs) can also induce EOMES expression as is shown by the reduced EOMES levels in T AIM cells lacking the receptor or signaling pathway required for type 1 IFN pathway.…”

“…EOMES is required for T AIM differentiation at several levels. EOMES has been shown to bind directly to the promotor and internal regions of Bcl2 and drive Bcl2 expression (pro-survival protein), thereby giving memory cells a survival advantage compared to the strongly stimulated effector cells [ 76 ]. Besides driving pro-survival signals, EOMES is also involved in upregulation of CD122, which is part of the IL-15 receptor and upregulated in T AIM cells [ 15 , 29 , 34 , 37 ].…”