Journal Article

Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R–STAT5B-driven neoplasms

Pinheiro, Rúben, Mullighan, Charles G., Cachucho, Ana, Kimura, Shunsuke, Blankenhaus, Birte, Pennington, Daniel J., Fiala, Gina J., Minguet, Susana, Coffelt, Seth B., Suske, Tobias, Moriggl, Richard, Silva-Santos, Bruno, Sumaria, Nital, Courtois, Lucien, Wiesheu, Robert, Darrigues, Julie, Barata, João T., Almeida, Afonso R. M., Curado-Avelar, Marta, Inácio, Daniel, Asnafi, Vahid, Lhermitte, Ludovic

2024

Overview

The contribution of γδ T cells to immune responses is associated with rapid secretion of interferon-γ (IFN-γ). Here, we show a perinatal thymic wave of innate IFN-γ-producing γδ T cells that express CD8αβ heterodimers and expand in preclinical models of infection and cancer. Optimal CD8αβ + γδ T cell development is directed by low T cell receptor signaling and through provision of interleukin (IL)-4 and IL-7. This population is pathologically relevant as overactive, or constitutive, IL-7R–STAT5B signaling promotes a supraphysiological accumulation of CD8αβ + γδ T cells in the thymus and peripheral lymphoid organs in two mouse models of T cell neoplasia. Likewise, CD8αβ + γδ T cells define a distinct subset of human T cell acute lymphoblastic leukemia pediatric patients. This work characterizes the normal and malignant development of CD8αβ + γδ T cells that are enriched in early life and contribute to innate IFN-γ responses to infection and cancer. Here the authors identify and characterize the development and function of an IFN-γ-producing CD8αβ + subset of γδ T cells that contributes to malignancy.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/1619/554/2509 / 631/250/232/2058 / 692/699/67/1990/283 / Acute lymphoblastic leukemia / Animal models / Animals / Biomedical and Life Sciences / Biomedicine / CD8 Antigens - metabolism / CD8-Positive T-Lymphocytes - immunology / Cell culture / Female / Humans / Immunity, Innate / Immunology / Infectious Diseases / Interferon-gamma - immunology / Interferon-gamma - metabolism / Interleukin-7 - metabolism / Intraepithelial Lymphocytes - immunology / Intraepithelial Lymphocytes - metabolism / Leukemia / Lymphatic leukemia / Lymphocytes / Lymphocytes T / Malignancy / Mice / Mice, Inbred C57BL / Mice, Knockout / Pediatrics / Receptors, Antigen, T-Cell, alpha-beta - genetics / Receptors, Antigen, T-Cell, alpha-beta - metabolism / Receptors, Antigen, T-Cell, gamma-delta - immunology / Receptors, Antigen, T-Cell, gamma-delta - metabolism / Receptors, Interleukin-7 - metabolism / Signal Transduction - immunology / STAT5 Transcription Factor - metabolism / T cell receptors / Thymus / Thymus Gland - immunology / γ-Interferon