• Tumors harbor a CD86 high CD8 + T-cell subset with suppressive features. • IL-12–IRF5 signaling induces CD86 on CD8 + T cells. • CD86 high CD8 + cells dampen antigen-specific OT-I/OT-II responses. • They drive DCs toward IDO/IL-10/CTLA-4/CD39-high states. • CD8-restricted Cd86 deletion curbs tumors and restores effector function. The tumor microenvironment (TME) promotes immune evasion by fostering regulatory immune programs. Although CD8 + regulatory T cells have been described, their identity, upstream drivers and impact in tumors remain incompletely defined. To define the phenotype, regulation determinants, and functional of CD86 high CD8 + T cells in tumor immunity. Murine tumor models were used to isolate tumor-infiltrating lymphocytes (TILs) for flow cytometry (FCM), functional co-cultures, and RNA-seq. Upstream cues were probed through cytokine stimulation and transcription factor analyses. Dendritic cells (DCs) conditioning was tested with bone marrow derived DCs and OT-I/OT-II antigen-specific systems. The in vivo function of CD86 on CD8 + T cells was evaluated using conditional Cd86 knockout in CD8 + T cells mouse model. CD86 was markedly upregulated on tumor-infiltrating CD8 + T cells, defining a CD86 high subset that accumulated in tumors. Transcriptomic profiling revealed enrichment of immunoregulatory and terminal-exhaustion programs while preserving effector modules. CD86 high cells upregulated Il12rb1 and IRF5; exogenous IL-12 increased the frequency and intensity of CD86 expression showing dose and time dependent effects, whereas IRF5 inhibition curtailed this induction, establishing an IL-12–IRF5 axis controlling CD86. Functionally, CD86 high CD8 + T cells selectively suppressed antigen-specific OT-I/OT-II responses, reducing IFN-γ, IL-2, and Ki-67, and reprogrammed DCs toward a regulatory phenotype characterized by increased IDO, IL-10, CTLA-4, and CD39. Genetic ablation of Cd86 in CD8 + T cells reduced tumor growth, diminished CD39 and PD-1 on TILs, enhanced IFN-γ and granzyme B, and remodeled the myeloid compartment toward immunostimulatory DCs with elevated CD40/CD80/CD86 and reduced IDO/IL-10/CTLA-4/CD39. CD86 high CD8 + T cells constitute a distinct immunoregulatory subset in cancer. Their differentiation is driven by an IL-12-IRF5 program, and their crosstalk with DCs via CD86/CTLA-4 engagement promotes tolerogenic remodeling of the TME. Targeting CD86 on CD8 + T cells may disrupt this suppressive circuit and potentiate antitumor immunity.
Hu et al. (Wed,) studied this question.