Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted T cell fate

This study aims to define how Id2 and Id3 regulate exhausted CD8+ T cell fate. We found that Id2 deletion reduced the Tex-eff population, whereas Id3 ablation in CD4-Cre mice diminished Tpex cells, indicating subset-specific roles for Id2 and Id3. Mechanistically, E2A is a major target of Id2/3, and Runx3 interacts with E2A. Pulldown of Id2/3 recovered both E2A and Runx3, supporting an Id2/3?E2A?Runx3 regulatory complex. To map the genomic occupancy of Id2 and Id3, we expressed 3×T7-tagged Id2 or Id3 in in vitro-primed CD45.2+ P14 cells, adoptively transferred these cells into CD45.1 recipient mice, and infected the recipients with LCMV Clone 13. On day 6 post-infection, Tex-eff and Tpex cells were isolated for T7 CUT&RUN to define Id2 binding in Tex-eff cells and Id3 binding in Tpex cells, with the empty T7 vector backbone used as a negative control.