High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells
Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CA...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-12-01
|
| Series: | Molecular Therapy: Methods & Clinical Development |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2329050124002018 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846143039840452608 |
|---|---|
| author | Russell W. Cochrane Rob A. Robino Bryan Granger Eva Allen Silvia Vaena Martin J. Romeo Aguirre A. de Cubas Stefano Berto Leonardo M.R. Ferreira |
| author_facet | Russell W. Cochrane Rob A. Robino Bryan Granger Eva Allen Silvia Vaena Martin J. Romeo Aguirre A. de Cubas Stefano Berto Leonardo M.R. Ferreira |
| author_sort | Russell W. Cochrane |
| collection | DOAJ |
| description | Regulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28-activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3+ CAR Tregs uniquely acquiring CD40L surface expression and producing IFN-γ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy. |
| format | Article |
| id | doaj-art-e83f1c9eae254dd28e271f8109a4c246 |
| institution | Kabale University |
| issn | 2329-0501 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Methods & Clinical Development |
| spelling | doaj-art-e83f1c9eae254dd28e271f8109a4c2462024-12-03T04:28:53ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012024-12-01324101385High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cellsRussell W. Cochrane0Rob A. Robino1Bryan Granger2Eva Allen3Silvia Vaena4Martin J. Romeo5Aguirre A. de Cubas6Stefano Berto7Leonardo M.R. Ferreira8Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USABioinformatics Core, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USAHollings Cancer Center, Medical University of South Carolina, Charleston, SC, USAHollings Cancer Center, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USABioinformatics Core, Medical University of South Carolina, Charleston, SC, USA; Department of Neuroscience, Medical University of South Carolina, Charleston, SC, USADepartment of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA; Corresponding author: Leonardo M.R. Ferreira, Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USARegulatory T cells (Tregs) are promising cellular therapies to induce immune tolerance in organ transplantation and autoimmune disease. The success of chimeric antigen receptor (CAR) T cell therapy for cancer has sparked interest in using CARs to generate antigen-specific Tregs. Here, we compared CAR with endogenous T cell receptor (TCR)/CD28 activation in human Tregs. Strikingly, CAR Tregs displayed increased cytotoxicity and diminished suppression of antigen-presenting cells and effector T (Teff) cells compared with TCR/CD28-activated Tregs. RNA sequencing revealed that CAR Tregs activate Teff cell gene programs. Indeed, CAR Tregs secreted high levels of inflammatory cytokines, with a subset of FOXP3+ CAR Tregs uniquely acquiring CD40L surface expression and producing IFN-γ. Interestingly, decreasing CAR antigen affinity reduced Teff cell gene expression and inflammatory cytokine production by CAR Tregs. Our findings showcase the impact of engineered receptor activation on Treg biology and support tailoring CAR constructs to Tregs for maximal therapeutic efficacy.http://www.sciencedirect.com/science/article/pii/S2329050124002018regulatory T cellchimeric antigen receptorreceptor affinitysynthetic immunologyimmune cell therapyimmune tolerance |
| spellingShingle | Russell W. Cochrane Rob A. Robino Bryan Granger Eva Allen Silvia Vaena Martin J. Romeo Aguirre A. de Cubas Stefano Berto Leonardo M.R. Ferreira High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells Molecular Therapy: Methods & Clinical Development regulatory T cell chimeric antigen receptor receptor affinity synthetic immunology immune cell therapy immune tolerance |
| title | High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells |
| title_full | High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells |
| title_fullStr | High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells |
| title_full_unstemmed | High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells |
| title_short | High-affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory T cells |
| title_sort | high affinity chimeric antigen receptor signaling induces an inflammatory program in human regulatory t cells |
| topic | regulatory T cell chimeric antigen receptor receptor affinity synthetic immunology immune cell therapy immune tolerance |
| url | http://www.sciencedirect.com/science/article/pii/S2329050124002018 |
| work_keys_str_mv | AT russellwcochrane highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT robarobino highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT bryangranger highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT evaallen highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT silviavaena highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT martinjromeo highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT aguirreadecubas highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT stefanoberto highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells AT leonardomrferreira highaffinitychimericantigenreceptorsignalinginducesaninflammatoryprograminhumanregulatorytcells |