Liu, S.; Elsaesser, H.; Quevedo, R.; Abd Rabbo, D.; Bertol, B.; Xu, W.; Liu, M.; Lukhele, S.; Lamorte, S.; McGaha, T.; Brooks, D. G.

Type I interferon (IFN I) and interferon-gamma are central regulators of antiviral immunity, yet how they cooperatively govern CD8 T cell fate during chronic infection remains unresolved. Here, we uncover a previously unrecognized, spatially encoded interferon circuit that actively constrains progenitor exhausted CD8 T cells (Tpex) during chronic LCMV infection. Persistent IFN I signaling indirectly restricts Tpex expansion by enforcing their sequestration within PDL1 rich B cell niches of lymphoid tissue and by suppressing T cell derived IFN gamma;. Blockade of IFN I signaling enables Tpex migration into T cell zones of splenic follicles driving IFN gamma; production, which in turn sustains PDL1 expression on myeloid cells to re-impose local inhibitory pressure. Combined IFN-I and IFN gamma; blockade disrupts this feedback, promoting coordinated niche redistribution of Tpex and checkpoint remodeling that drives robust Tpex expansion. Single-cell transcriptomics reveal that this layered IFN I with IFN gamma interplay establishes a regulatory balance that constrains Tpex proliferation while preserving effector like transcriptional programs in their progeny effector CD8 T cells, ultimately preventing premature terminal differentiation. Thus, interferons orchestrate the coordinated T cell to myeloid regulatory circuit that integrates tissue organization, cytokine feedback, and checkpoint control to regulate CD8 T cell exhaustion during chronic infection.