The Effect of B7H6 Ligand on T Cell Responses

Infectious Diseases Rheumatology and Immunology Life Sciences Immunology Oncology Medicine
B7H6 T cells immune surveillance NK cells cancer immunology antitumor response

Immunoglobulin Superfamily Ligand B7H6 Enables T Cell Responses under NK Cell Surveillance

Background

In the field of immunology, understanding the mechanisms regulating T cell immunity is crucial for developing effective therapies for diseases related to T cell dysfunction, such as autoimmune diseases, chronic infections, and cancer. T cells mediate specific immune responses in viral infections, tumors, and autoimmunity, undergoing strictly regulated expansion and persistence following antigen recognition. Inhibitory immune cells (e.g., regulatory T cells and certain myeloid cells) can upregulate checkpoint molecules or inhibitory cytokines to dampen T cell responses, maintaining homeostasis and self-tolerance. However, dysregulated T cell activation can lead to T cell-driven autoimmunity or ineffective anti-tumor responses.

Research Origin

This study was conducted by Michael Kilian, Mirco J. Friedrich, Kevin Hai-Ning Lu, and other researchers from institutions such as the German Cancer Research Center (DKFZ), the Broad Institute of Harvard University, and Heidelberg University Medical School. The study was published in the May 3, 2024, issue of Science Immunology.

Research Process

Study Design and Process

The study aimed to screen for mediators on T cells that could be recognized by natural killer (NK) cells, revealing the function of the immunoglobulin superfamily ligand B7H6 on T cells.

  1. T Cell Activation:

    • Evaluated the expression of 27 NK cell ligands on resting and stimulated T cells from healthy donors using flow cytometry.
    • Detected a significant upregulation of B7H6 on activated T cells after 72 hours of stimulation with anti-CD3/CD28 beads.

  2. Ligand Screening:

    • The screening results showed that B7H6 exhibited the highest upregulation and absolute surface expression levels among all screened NK cell ligands.

  3. Functional Validation:

    • Validated B7H6 surface expression on activated T cells using immunofluorescence.
    • Observed that genetic deletion of B7H6 in humanized mouse models enhanced T cell proliferation and persistence.

Results and Data Analysis

  1. B7H6 Expression:

    • Single-cell RNA sequencing data analysis revealed that B7H6 surface protein expression was primarily limited to effector CD8+ lymphocytes. A significant proportion of B7H6+ T cells was observed in various diseases, such as chronic hepatitis B infection, bladder cancer, and B cell lymphoma.

  2. NK Cell Recognition and Killing of Activated T Cells:

    • Co-culture experiments showed that NK cells could recognize and kill activated T cells through the NKp30-B7H6 axis.
    • CRISPR-Cas9 mediated B7H6 gene deletion experiments indicated that B7H6 knockout T cells were resistant to NK cell-mediated killing.

  3. Role of B7H6 in Tumor Microenvironment:

    • In esophageal cancer patients, the frequency of B7H6+ tumor-infiltrating T cells correlated positively with clinical response, especially CD8+ T cells.
    • A high NK/T cell ratio was associated with poorer progression-free survival.

Research Conclusion

This study demonstrates that B7H6, as an NK cell-dependent immune checkpoint, regulates human T cell function by inducing NK cell-mediated cytolysis. This finding reveals a negative regulatory role of NK cells in T cell expansion and persistence, proposing the B7H6-NKP30 axis as a potential therapeutic target to enhance the persistence of CAR-T cell therapies.

Research Significance

The scientific value of this study lies in:

  1. Revealing a New Immunoregulatory Mechanism:

    • Identifying B7H6 as an NK cell-dependent immune checkpoint that regulates T cell function through NK cell-mediated cytolysis.

  2. Providing a Potential Therapeutic Target:

    • Proposing the B7H6-NKP30 axis as a treatable immune checkpoint, which could be used to improve the persistence and efficacy of CAR-T cell therapies.

Research Highlights

  1. High Expression and Function of B7H6:

    • The high expression of B7H6 on activated T cells is directly related to NK cell recognition and cytolysis.
    • CRISPR-Cas9 gene editing successfully deleted the B7H6 gene, making T cells resistant to NK cell-mediated killing.

  2. Clinical Relevance:

    • In esophageal cancer patients, the frequency of B7H6+ tumor-infiltrating T cells correlates positively with clinical response, especially CD8+ T cells.
    • A high NK/T cell ratio is associated with poorer progression-free survival.

Conclusion and Future Prospects

By deeply investigating the role of B7H6 in T cell and NK cell interactions, this study unveils a novel immunoregulatory mechanism. This discovery not only provides new insights into T cell function regulation but also offers a significant basis for developing new immunotherapeutic strategies. Future research could further explore the role of B7H6 in other diseases and develop specific therapies targeting B7H6 to enhance the efficacy of immunotherapies.