GSE160758
Inhibitory signaling sustains a distinct early memory CD8+ T cell precursor that is resistant to DNA damage
The developmental origins of memory T cells remain controversial. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8+ T cells that possessed unique characteristics including expression of CD62L, TCF-1 and Eomes; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including PD-1, LAG-3, CTLA-4, CD5, and CD160.  Indeed, genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells (TCM) were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results suggest a parsimonious model wherein there is more than a single developmental origin of long-term memory CD8+ T cells, and point to novel links between genome integrity, regulation of signal intensity during priming, inhibitory receptors and generation of long-term CD8+ T cell memory. To gain deeper insight into the biology of this CD62Lhi subset, we performed RNAseq on purified CD62Lhi, IL-7Rahi and KLRG1hi subsets on day 8 post LCMV Arm infection and included naive P14 CD8+ T cells from uninfected mice as a control. Overall design: CD62Lhi, IL-7Rahi and KLRG1hi P14 CD8+ T cell subsets were sorted from d8 LCMV Arm infected mice on day 8 pi and naive P14 CD8+ T cells were sorted from uninfected P14 mice. Three biological replicates were analyzed for each of the defined CD8+ T cell subsets.