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Therapeutic Targeting of Follicular Helper T Cells with Chimeric Antigen Receptor-Expressing Natural Killer Cells

35 Pages Posted: 21 Feb 2019 Sneak Peek Status: Review Complete

See all articles by Seth D. Reighard

Seth D. Reighard

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

Stacey A. Cranert

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

Kelly M. Rangel

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

Ayad Ali

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

Arthur T. de la Cruz-Lynch

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

Jasmine A. Tuazon

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

Leah C. Kottyan

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

David F. Smith

University of Cincinnati - Department of Pediatrics

Hermine I. Brunner

University of Cincinnati - Department of Pediatrics

Stephen Waggoner

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

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Abstract

Follicular helper T cells (TFH) are critical for vaccine and infection elicitation of long-lived humoral immunity, but exaggerated TFH responses can promote autoimmunity and other pathologies. Unfortunately, no clinical interventions are currently available for selective depletion of TFH cells to alleviate these disease conditions. We engineered a novel chimeric antigen receptor (CAR) that facilitates specific targeting of cells highly expressing human programmed cell death protein 1 (PD-1), a cardinal feature of TFH cells. CAR-expressing natural killer (NK) cells robustly degranulate in response to PD-1, resulting in discriminatory elimination of human tonsil TFH cells while sparing other T and B-cell subsets. Given that CAR NK cells are emerging as a safe and effective alternative to CAR T cells in cancer immunotherapy, our results suggest a new, clinically-translatable application of CAR NK cells for selective depletion of pathogenic TFH cells in specific disease states.

Keywords: Systemic lupus erythematosus; rheumatoid arthritis; Sjögren’s syndrome; allergy; cytotherapy; cytotoxicity; checkpoint; PD-L1; NK-92

Suggested Citation

Reighard, Seth D. and Cranert, Stacey A. and Rangel, Kelly M. and Ali, Ayad and Cruz-Lynch, Arthur T. de la and Tuazon, Jasmine A. and Kottyan, Leah C. and Smith, David F. and Brunner, Hermine I. and Waggoner, Stephen, Therapeutic Targeting of Follicular Helper T Cells with Chimeric Antigen Receptor-Expressing Natural Killer Cells (February 21, 2019). Available at SSRN: https://ssrn.com/abstract=3335775 or http://dx.doi.org/10.2139/ssrn.3335775
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Seth D. Reighard

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Stacey A. Cranert

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Kelly M. Rangel

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Ayad Ali

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Arthur T. de la Cruz-Lynch

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Jasmine A. Tuazon

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

Leah C. Kottyan

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology

3333 Burnet Avenue
Cincinnati, OH 45229
United States

David F. Smith

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Hermine I. Brunner

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Stephen Waggoner (Contact Author)

Cincinnati Children's Hospital Medical Center - Center for Autoimmune Genomics and Etiology ( email )

3333 Burnet Avenue
Cincinnati, OH 45229
United States

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