Zhang et al. demonstrated the differentiation of Type-1 regulatory T cells (Tr1) from an Eomes+IL-10- precursor state to Eomes+IL-10+ subsets with both regulatory and cytotoxic functions in bone marrow transplantation (BMT). Eomes+ CD4+ T cells were the major cytotoxic CD4+ T cell subset post BMT, mediating both GVL and anti-inflammatory effects via perforin-dependent APC depletion. In adoptive T cell therapy, Eomes+CD4+ CAR T cells adopted Tr1-like phenotypes that limited toxicity while sustaining cytolytic functions and persistence for durable tumor control. Eomes+CD4+ CD19-targeted CAR T cells were persistent in long-term survivors of B cell malignancies.
Contributed by Shishir Pant
ABSTRACT: Interleukin 10 (IL-10)-producing CD4(+) type-1 regulatory T cells (Tr1) promote immune tolerance during chronic infection, autoimmunity, and transplantation. However, specific Eomesodermin (Eomes)-dependent stages of Tr1 differentiation and function remain unclear. Using preclinical models of bone marrow transplantation (BMT), we demonstrated a Tr1 differentiation trajectory in vivo from Eomes(+)IL-10(-) to Eomes(+)IL-10(+) subsets with the acquisition of cytokine, cytolytic, and exhaustion features. The Eomes(+)CD4(+) fraction represented the dominant cytotoxic subset after BMT, mediating graft-versus-leukemia effects while limiting inflammation. In CD19-targeted chimeric antigen receptor (CAR) T cell immunotherapy, Eomes drove the same CD4(+) Tr1 phenotype that controlled cytolysis, while mitigating immune toxicity and promoting persistence. In individuals with high-grade B cell lymphomas that had long-term disease control after receiving commercial CD19-targeted CAR T cells, Eomes(+) Tr1 cells represented a stable population comprising 40%-80% of the CD4(+) CAR T cell population. Hence, Eomes controls both regulatory and cytotoxic programs in CD4(+) T cells, essential for curative immunotherapy outcomes.
Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006,
Author Info: (1) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. Electronic address: pzhang@fredhutch.org. (2) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (3) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (4) QIMR Berghofer Medical Research Institute, Herston, Brisbane, QLD 4006, Australia. (5) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (6) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (7) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (8) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (9) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (10) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (11) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (12) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (13) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (14) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (15) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (16) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. (17) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (18) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (19) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA. (20) Envoi Pathology, Brisbane, QLD 4006, Australia. (21) Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. (22) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Department of Pediatrics, University of Washington, Seattle, WA 98105, USA. (23) Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Division of Medical Oncology, University of Washington, Seattle, WA 98109, USA. Electronic address: grhill@fredhutch.org.
