Selective elimination of circulating effector CD8 T cells via LTβR blockade separates anti-CD137 efficacy from...

The major barrier to clinical translation of αCD137 immunotherapy is separating antitumor efficacy from hepatotoxicity driven by IFN-γ-producing CD8 T cells. We propose a strategy to limit toxicity by promoting contraction of excessively expanded CD8 T cells. We identify CD11c⁺KLRG1⁺ effector CD8 T cells (CD11c⁺T_E) as the primary source of IFN-γ, recirculating between blood and secondary lymphoid organs (SLOs), where they undergo apoptosis during contraction. We show that lymphotoxin β receptor (LTβR) signaling restrains this contraction. Mechanistically, lymphotoxin-expressing B cells activate LTβR in fibroblastic reticular cells (FRCs), suppressing apoptosis of CD11c⁺T_E cells in the spleen and sustaining their systemic circulation and liver infiltration. Pharmacological LTβR blockade abrogates hepatotoxicity by reducing the accumulation of IFN-γ-producing CD11c⁺T_E cells while preserving tumor-specific CD8 T cell responses. These findings identify LTβR as a key regulator of effector CD8 T cell persistence and support the use of LTβR antagonists to improve the safety of αCD137-based immunotherapy.