Abstract
Transmembrane protein GARP binds latent TGF-β1 to form GARP:(latent)TGF-β1 complexes on the surface of several cell types including Tregs, B-cells, and platelets. Upon stimulation, these cells release active TGF-β1. Blocking TGF-β1 activation by Tregs with anti-GARP:TGF-β1 mAbs overcomes resistance to PD1/PD-L1 blockade and induces immune-mediated regressions of murine tumors, indicating that Treg-derived TGF-β1 inhibits anti-tumor immunity. TGF-β1 exerts a vast array of effects on immune responses. For example, it favors differentiation of TH17 cells and B-cell switch to IgA production, two important processes for mucosal immunity. Here, we sought to determine whether treatment with anti-GARP:TGF-β1 mAbs would perturb immune responses to intestinal bacterial infection. We observed no aggravation of intestinal disease, no systemic dissemination, and no alteration of innate or adaptative immune responses upon oral gavage of C. rodentium in highly susceptible Il22r−/− mice treated with anti-GARP:TGF-β1 mAbs. To examine the effects of GARP:TGF-β1 blockade on Ig production, we compared B cell- and TH cell- responses to OVA or CTB protein immunization in mice carrying deletions of Garp in Tregs, B cells, or platelets. No alteration of adaptive immune responses to protein immunization was observed in the absence of GARP on any of these cells. Altogether, we show that antibody-mediated blockade of GARP:TGF-β1 or genetic deletion of Garp in Tregs, B cells or platelets, do not alter innate or adaptive immune responses to intestinal bacterial infection or protein immunization in mice. Anti-GARP:TGF-β1 mAbs, currently tested for cancer immunotherapy, may thus restore anti-tumor immunity without severely impairing other immune defenses.PrécisImmunotherapy with GARP:TGF-β1 mAbs may restore anti-tumor immunity without impairing immune or inflammatory responses required to maintain homeostasis or host defense against infection, notably at mucosal barriers.
Highlights
Transforming growth factor-β1 (TGF-β1) is a potent immunosuppressive cytokine that plays an important role in the maintenance of immune tolerance [1, 2]
We tested whether TGF-β1 blockade with anti-GARP:TGF-β1 mAbs would increase the severity of disease in these mice
These results indicate that antiGARP:TGF-β1 mAbs do not reduce control of bacterial proliferation nor does it aggravate the severity of disease induced by C. rodentium infection in wild-type C57BL/6 (WT) mice or in highly susceptible Il22r−/− mice
Summary
Transforming growth factor-β1 (TGF-β1) is a potent immunosuppressive cytokine that plays an important role in the maintenance of immune tolerance [1, 2]. Most cells, including immune cells, produce TGF-β1 in a latent, inactive form, in which the mature TGF-β1 dimer is non-covalently associated with the latency-associated peptide (LAP) [3, 4]. In addition to blocking Treg immunosuppression and restoring anti-tumor immunity, antiGARP:TGF-β1 mAbs could exert unwanted side effects, owing on one hand to their ability to block TGF-β1 activation from non-Treg GARP-expressing cells, and on the other hand to the pleiotropic functions exerted by TGF-β1 in immunity, including adaptive immunity. TGF-β1 is known to induce switch to IgA production in B cells, and differentiation of naïve CD4+ T cells into TH17 effectors in presence of IL-6 or into peripheral Tregs (pTregs) in presence of IL-2 [13,14,15]. TH17, pTregs and IgA-producing B cells are adaptive immune effectors playing important roles in the establishment and maintenance of balanced immune responses at epithelial barriers. The use of blocking anti-GARP:TGF-β1 mAbs for the purpose of cancer immunotherapy could perturb immunity against bacterial infections in the intestine
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