CD19 CAR Engineered T Regulatory Cells Promote Durable Immune Tolerance in Experimental Systemic Lupus Erythematosus
- 1University of Washington
Abstract
While the immune reset induced by CD19 CAR T therapies has shown striking promise in systemic lupus erythematosus (SLE), the nature and duration of benefit mediated by B cell depletion remains unclear. Loss of tolerance in SLE is driven by extrafollicular and germinal center interactions between dendritic cells and self-reactive T and B cells. We hypothesized that CD19 CAR-engineered regulatory T cells (CAR19 EngTreg), capable of suppressing multiple autoimmune effector cell types, might promote long-term tolerance without producing high-levels of inflammatory mediators. To generate CAR19 EngTreg, we combined CD19 CAR delivery with homology directed repair at the FOXP3 locus to drive constitutive, stable FOXP3 expression in CD4 T cells. CAR19 EngTreg expressed canonical Treg markers; exhibited minimal inflammatory cytokine production; and blocked human B cell differentiation into antibody secreting plasma cells. In humanized mouse models, transfer of CAR19 EngTreg led to a reduction in B cell numbers with low inflammatory cytokine production relative to CD19 CAR Teff, and reduced tissue inflammation. In a short-term, in vivo imiquimod-induced inflammatory model, murine CAR19 EngTreg reduced skin pathology, spleen size, and inflammatory cytokines. Finally, in two distinct mouse models of lupus, CAR19 EngTreg persisted for >4 months leading to reduced autoimmune T and B effector populations, sustained reduction in multiple autoantibodies and improved renal function and histopathology. Thus, CAR19 EngTreg may offer a promising and durable therapeutic avenue for B cell-mediated autoimmune disorders capable of long-term regulation of both autoreactive B and T cells.
Related
- Single-cell multi-ancestry regulatory map of systemic lupus erythematosus
- Regulatory T cell dysfunction and therapeutic advances in rheumatoid arthritis, psoriasis, vitiligo, and systemic lupus erythematosus
- Immunological cross-talk between periodontitis and systemic lupus erythematosus: the role of T–B cell dysregulation in the shared pathogenic network
- Mosaic KRAS variants in childhood-onset systemic lupus erythematosus.
- Thrombotic microangiopathy in a patient with systemic lupus erythematosus and systemic sclerosis overlap syndrome: a case report and review of the literature
BibTeX
@misc{drow2026cd19,
title = {{CD19 CAR Engineered T Regulatory Cells Promote Durable Immune Tolerance in Experimental Systemic Lupus Erythematosus}},
author = {T. Drow and M. Doglio and A. Grimm and V. DeVault-Nelson and M. Hoover and B. McKinney and S. K. Tripathi and J. Mellen and M. Milazewski and P. Zarin and A. Burgess and C. L. Moore and P. Carulli and A. Ugolini and C. Bercher and A. Vakil and N. P. Dahl and S. M. Ponnan and N. Mungra and S. Akilesh and Y. Chen and P. Knebusch and S. W. Jackson and C. Patel and T. Chen and A. Del Rio-Espinola and C. Bonini and T. Wickham and P. J. Cook and D. J. Rawlings},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.05.756761},
url = {https://www.biorxiv.org/content/10.64898/2026.10.05.756761v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - CD19 CAR Engineered T Regulatory Cells Promote Durable Immune Tolerance in Experimental Systemic Lupus Erythematosus
AU - T. Drow
AU - M. Doglio
AU - A. Grimm
AU - V. DeVault-Nelson
AU - M. Hoover
AU - B. McKinney
AU - S. K. Tripathi
AU - J. Mellen
AU - M. Milazewski
AU - P. Zarin
AU - A. Burgess
AU - C. L. Moore
AU - P. Carulli
AU - A. Ugolini
AU - C. Bercher
AU - A. Vakil
AU - N. P. Dahl
AU - S. M. Ponnan
AU - N. Mungra
AU - S. Akilesh
AU - Y. Chen
AU - P. Knebusch
AU - S. W. Jackson
AU - C. Patel
AU - T. Chen
AU - A. Del Rio-Espinola
AU - C. Bonini
AU - T. Wickham
AU - P. J. Cook
AU - D. J. Rawlings
PY - 2026
DA - 2026/10/05
PB - bioRxiv
DO - 10.64898/2026.10.05.756761
UR - https://www.biorxiv.org/content/10.64898/2026.10.05.756761v1
AB - While the immune reset induced by CD19 CAR T therapies has shown striking promise in systemic lupus erythematosus (SLE), the nature and duration of benefit mediated by B cell depletion remains unclear. Loss of tolerance in SLE is driven by extrafollicular and germinal center interactions between dendritic cells and self-reactive T and B cells. We hypothesized that CD19 CAR-engineered regulatory T cells (CAR19 EngTreg), capable of suppressing multiple autoimmune effector cell types, might promote long-term tolerance without producing high-levels of inflammatory mediators. To generate CAR19 EngTreg, we combined CD19 CAR delivery with homology directed repair at the FOXP3 locus to drive constitutive, stable FOXP3 expression in CD4 T cells. CAR19 EngTreg expressed canonical Treg markers; exhibited minimal inflammatory cytokine production; and blocked human B cell differentiation into antibody secreting plasma cells. In humanized mouse models, transfer of CAR19 EngTreg led to a reduction in B cell numbers with low inflammatory cytokine production relative to CD19 CAR Teff, and reduced tissue inflammation. In a short-term, in vivo imiquimod-induced inflammatory model, murine CAR19 EngTreg reduced skin pathology, spleen size, and inflammatory cytokines. Finally, in two distinct mouse models of lupus, CAR19 EngTreg persisted for >4 months leading to reduced autoimmune T and B effector populations, sustained reduction in multiple autoantibodies and improved renal function and histopathology. Thus, CAR19 EngTreg may offer a promising and durable therapeutic avenue for B cell-mediated autoimmune disorders capable of long-term regulation of both autoreactive B and T cells.
ER -