Intercellular trafficking of latent TGF-β1 converts integrin expressing cells into signaling relays

TGF-{beta}1 is secreted as a latent complex tethered to the cell surface by milieu molecules such as GARP, and its activation requires direct engagement by integrin-expressing cells. How this interaction converts the latent complex into signaling-competent growth factor (GF) remains unclear. Here we show that contact between GARP/TGF-{beta}1-presenting cells and cells expressing integrin V{beta}6 or V{beta}8 triggers rapid trogocytosis of the latent complex, both in transfected cells and two cancer cell lines that natively express these integrins. Independent labeling of the prodomain, GF, and GARP shows that all three components are co-transferred to the integrin-expressing cell, and a TGF-{beta}1 mutant (RGE) that cannot bind integrins shows little transfer. Using a reporter system that tracks pathway activation in presenting, integrin-expressing, and bystander cells, we find that GF-neutralizing antibodies block downstream signaling more effectively in bystander cells than in the first two cell types that participate in trogocytosis. Blocking cleavage between the prodomain and the GF blocks signaling in bystander cells while still permitting signaling in trogocytosing cell types. Finally, we integrin-expressing cells that have taken up latent TGF-{beta}1 by trogocytosis can activate it and signal to bystander cells after the TGF-{beta}1 cells are removed, indicating that trogocytosis converts integrin-expressing cells into TGF-{beta} signaling relays. These findings identify a role for trogocytosis in regulating the specificity of TGF-{beta}1 activation and signaling, and reveal a novel function of integrins in controlling protein localization.