BCL11B depletion induces the development of highly cytotoxic innate T cells out of IL-15 stimulated peripheral blood αβ CD8+ T cells. (31st December 2022)

• Record Type: Journal Article
• Authors: Forkel, Hannes; Grabarczyk, Piotr; Depke, Maren; Troschke-Meurer, Sascha; Simm, Stefan; Hammer, Elke; Michalik, Stephan; Hentschker, Christian; Corleis, Björn; Loyal, Lucie; Zumpe, Maxi; Siebert, Nikolai; Dorhoi, Anca; Thiel, Andreas; Lode, Holger; Völker, Uwe; Schmidt, Christian A.
• Is Part Of: Oncoimmunology. Volume 11:Number 1(2022)
• Publication Date: 2022-12-31
• Subjects: BCL11B -- knock-out -- IL-15 -- innateness -- AICC -- ADCC -- CRISPR/Cas9 -- human -- alpha-beta CD8+ T cells; Tumors -- Immunological aspects -- Periodicals; Neoplasms -- therapy -- Periodicals; Immunotherapy -- Periodicals; 616.994
• DOI: 10.1080/2162402X.2022.2148850
• Languages: English
• ISSNs: 2162-402X

Abstract

ABSTRACT: BCL11B, an essential transcription factor for thymopoiesis, regulates also vital processes in post-thymic lymphocytes. Increased expression of BCL11B was recently correlated with the maturation of NK cells, whereas reduced BCL11B levels were observed in native and induced T cell subsets displaying NK cell features. We show that BCL11B-depleted CD8+ T cells stimulated with IL-15 acquired remarkable innate characteristics. These induced innate CD8+ (iiT8) cells expressed multiple innate receptors like NKp30, CD161, and CD16 as well as factors regulating migration and tissue homing while maintaining their T cell phenotype. The iiT8 cells effectively killed leukemic cells spontaneously and neuroblastoma spheroids in the presence of a tumor-specific monoclonal antibody mediated by CD16 receptor activation. These iiT8 cells integrate the innate natural killer cell activity with adaptive T cell longevity, promising an interesting therapeutic potential. Our study demonstrates that innate T cells, albeit of limited clinical applicability given their low frequency, can be efficiently generated from peripheral blood and applied for adoptive transfer, CAR therapy, or combined with therapeutic antibodies.