Phenotypically and functionally unique CD86 expression CD8 T cell subset shapes immune regulation in the tumor microenvironment

  • J Adv Res. 2026 Apr 5:S2090-1232(26)00285-7. doi: 10.1016/j.jare.2026.04.006.
Xin Hu  1 ,  Yifang Shui  2 ,  Yixian Fan  1 ,  Shuji Takada  3 ,  Miho Terao  3 ,  Miyuki Shindo  4 ,  Weitao Que  5 ,  Masayuki Fujino  6 ,  Wen-Zhi Guo  7 ,  Xiao-Kang Li  8
Affiliations
  • 1. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 2. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
  • 3. Department of Systems Developmental Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 4. Division of Laboratory Animal Resources, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 5. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Liver Surgery & Organ Transplantation Center, Shenzhen Third People's Hospital, Shenzhen, China.
  • 6. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Management Department of Biosafety, Laboratory Animal, and Pathogen Bank, National Institute of Infectious Diseases, Tokyo, Japan. Electronic address: [email protected].
  • 7. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: [email protected].
  • 8. Division of Transplantation Immunology, National Research Institute for Child Health and Development, Tokyo, Japan; Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. Electronic address: [email protected].
PMID: 41942048 DOI: 10.1016/j.jare.2026.04.006
Abstract

Introduction: 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.

Objectives: To define the phenotype, regulation determinants, and functional of CD86high CD8+ T cells in tumor immunity.

Methods: 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.

Results: CD86 was markedly upregulated on tumor-infiltrating CD8+ T cells, defining a CD86high subset that accumulated in tumors. Transcriptomic profiling revealed enrichment of immunoregulatory and terminal-exhaustion programs while preserving effector modules. CD86high 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, CD86high 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.

Conclusions: CD86high 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.

Keywords
CD8(+) T cells; CD86; Immunoregulation; Tumor microenvironment.
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