Role of GARP in regulating autoimmunity and immune responses to infection or protein immunisation
(2021)
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- Authors
- Supervisors
- Lucas, Sophie
- Abstract
- Transforming Growth Factor β1 (TGF-β1) is a pleiotropic cytokine which plays important roles in the immune system. Transmembrane protein GARP presents latent TGF-β1 for activation by integrins on the surface of TCR-stimulated Tregs, BCR-stimulated B cells, and platelets. Our laboratory previously showed that TGF-β1 produced from GARP:(latent) TGF-β1 complexes participates to immunosuppression by Tregs in tumor-bearing mice. They developed blocking anti-GARP:TGF-β1 monoclonal antibodies (mAbs) that are currently tested for the purpose of cancer immunotherapy in a phase I clinical trial in patients with cancer. Our laboratory also showed that TGF-β1 produced from GARP:TGF-β1 on human B cells contributes to class switch recombination and production of IgA, known to play important roles in immunity against infections at mucosal interfaces. Other groups reported roles for TGF-β1 produced by GARP-expressing platelets in suppressing anti-tumor immunity, and for TGF-β1 produced by GARP-expressing B cells or Tregs in preventing autoimmunity. Altogether, roles of TGF-β1 produced by the various GARP-expressing cells in regulating immune responses against tumors, infections or in autoimmune diseases are far from completely understood. The goals of this study were two-fold. On one hand, we attempted to determine whether administration of anti-GARP:TGF-β1 mAbs could alter immune responses to intestinal bacterial infections in mice. We found that the mAbs did not alter innate or adaptive immune responses nor did it aggravate disease induced by C. rodentium gavage. These observations are encouraging with regards to the risks of toxicity of anti-GARP:TGF-β1 mAbs in cancer patients. On the other hand, we performed a comparative analysis of the roles played by different GARP- expressing cells in preventing autoimmunity in mice. We used genetically modified mice carrying deletions of the Garp gene in Tregs, B cells or platelets and monitored the development of spontaneous autoimmunity upon aging, or after chronic exposure to strong inflammatory stimuli. We found that TGF-β1 produced by GARP-expressing B cells prevents spontaneous autoimmunity upon aging, whereas TGF-β1 produced by GARP-expressing Tregs prevents autoimmunity induced by persistent inflammation.
- Affiliations
Citations
Zhang, X. (2021). Role of GARP in regulating autoimmunity and immune responses to infection or protein immunisation. https://hdl.handle.net/2078.5/117913