Size-dependent segregation controls macrophage phagocytosis of antibody-opsonized targets
Preprint posted on 19 January 2018 https://www.biorxiv.org/content/early/2018/01/19/250373
Article now published in Cell at http://dx.doi.org/10.1016/j.cell.2018.05.059
Macrophages distinguish nanoscale distance between an antigen and its surface via physical exclusion of CD45
Selected by Tim Fessenden
Categories: cell biology, immunology
Context
Cell biologists have seen fit to describe many cell behaviors without recourse to the precise protein interactions through which they occur. A frustrating gap in understanding persists between established activities of individual proteins and cellular functions. Employing tricks of protein engineering, superresolution microscopy, and in vitro assemblies, a growing number of labs are now probing functional assemblies of proteins at this intermediate scale (for a great example, see work on the T-cell receptor by Ron Vale’s lab). Working in these gaps to reach across spatial and temporal scales should be a top priority of cell biology.
Bakalar and colleagues in the Fletcher lab help us in this challenge by asking a very simple question about how macrophages “see” antibody-coated surfaces. They explore whether antibodies that are bound to antigens far from the target surface (~20 nm) are differently treated by macrophages than those near the surface (~5 nm). One might expect this to make no difference whatsoever: macrophages efficiently engulf a huge variety of antibody-bound targets, in which the antigen that serves as the target might be huge, or a tiny protein.
Data
Using natural and engineered proteins to query this simple spatial relationship, Bakalar et al show a surprising bias toward phagocytosis when antigens are close to the target surface. They use an elegant combination of synthetic antigens and TIRF microscopy, and corroborate their findings by modifying a naturally occurring antigen. The authors also make creative use of a cell-free protocol to query protein-protein interactions across apposed plasma membranes, described in their previous publication (Schmid and Bakalar et al).
From a compelling final set of experiments, they conclude that clusters of Fc gamma receptors bound to shorter antigens can physically exclude a negative regulator (CD45) – which is taller – and thus more efficiently activate phagocytosis.
Implications
To this reader’s great satisfaction, observations reported here agree with work from the Cragg lab, who found that antibody-surface distance determined NK cell effector functions in vivo. This work carries interesting implications, as pointed out by the authors, for the success or failure of monoclonal antibody-based therapies, such as trastuzumab or ipilimumab, that are mediated by macrophages, natural killer cells, or other immune cell types. Most importantly, it brings focus and rigor to our thinking about the physical interfaces formed between a cell and its target surface (or another cell). In this regard, the authors cite work by Paszek and colleagues investigating the glycocalyx – the dense brush of glycoproteins covering a cell’s plasma membrane – that can govern the physics of cell-surface interactions.
Questions
- Are long cell surface proteins disfavored by pathogens?
- Does B cell development reflect this spatial skewing of antibody binding sites?
- Do tumor cells expressing longer tumor antigenic proteins escape immune surveillance (as suggested in part by Paszek et al)?
Carbone, C.B., Kern, N., Fernandes, R.A., Hui, E., Su, X., Garcia, K.C., and Vale, R. (2017). In vitro reconstitution of T cell receptor-mediated segregation of the CD45 phosphatase. PNAS 114 (44) E9338- E9345.
Cleary, K.L.S., Chan, H.T.C., James, S., Glennie, M.J., and Cragg, M.S. (2017). Antibody Distance from the Cell Membrane Regulates Antibody Effector Mechanisms. J. Immunol. 1950 198, 3999–4011.
Paszek, M.J., DuFort, C.C., Rossier, O., Bainer, R., Mouw, J.K., Godula, K., Hudak, J.E., Lakins, J.N., Wijekoon, A.C., Cassereau, L., et al. (2014). The cancer glycocalyx mechanically primes integrin- mediated growth and survival. Nature 511, 319–325.
Schmid, E.M., Bakalar, M.H., Choudhuri, K., Weichsel, J., Ann, H.S., Geissler, P.L., Dustin, M.L., and Fletcher, D.A. (2016). Size-dependent protein segregation at membrane interfaces. Nat. Phys.
Posted on: 7 February 2018 , updated on: 15 May 2018
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