Functional Type I and Type II interferon crosstalk restricts progenitor exhausted CD8 T cells through spatial exclusion and checkpoint enforcement

ABSTRACT Type I interferon (IFN-I) and interferon-γ (IFNγ) 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 IFNγ. Blockade of IFN-I signaling enables Tpex migration into T cell zones of splenic follicles driving IFNγ production, which in turn sustains PDL1 expression on myeloid cells to re-impose local inhibitory pressure. Combined IFN-I and IFNγ 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–IFNγ 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–myeloid regulatory circuit that integrates tissue organization, cytokine feedback, and checkpoint control to regulate CD8 T cell exhaustion during chronic infection. Competing Interest Statement The authors have declared no competing interest.