European Mast Cell and
Basophil Research Network

Role of tetraspanins in mast cells

Tetraspanins are modulators of mast cell degranulation

Mast cell (MC) degranulation basically is the result of FceRI cross-linking by IgE bound antigen. However, this process is mediated by a complex signaling machinery, sometimes referred to as the FceRI signalosome (1). Tetraspanin proteins have been named after their four transmembrane domains that incorporate several conserved motifs (2). They are often described as scaffold proteins that enable clustering of other membrane proteins, such bringing together various partners of intracellular signaling cascades (3) or increasing the density of some receptors (e.g. integrins) at some location at the extracellular side of the membrane (4). But tetraspanins are not restricted to the plasma membrane, they also reside in the membranes of intracellular compartments. An example for this is CD63, that is residing in the membranes of granules of various cell types as well and has long been known as an activation marker of human mast cells and basophils (5). However, CD63 and other tetraspanins are not just markers, but also modulators of MC degranulation by mediating clustering of FceRI and co-clustering of additional membrane molecules important for successful FceRI signaling. Surprisingly, they fine tune also additional MC functions (6). 


After FceRI crosslinking by IgE-Antibody complexes, CD63 containing membranes of MC or basophil granules fuse with the plasma membrane in the process of granule exocytosis. Interestingly, CD63 of granule origin possesses a glucosylation pattern different from CD63 molecules that always have resided in the plasma membrane. A new antibody specifically recognizes this CD63 of granular origin. It has been used to demonstrate that MC are able to degranulate more often than just once (7). CD63 is supposed to be co-localized with the FceRI. A blocking antibody against CD63 inhibits MC adhesion to the extracellular matrix (ECM) proteins fibronectin and vitronectin, possibly by disrupting integrin-clustering by CD63. It also neutralizes the degranulation promoting effect of MC adhesion to ECM, supposedly by inhibition of the Gab2-PI3K pathway that is a mediator of both adhesion and degranulation (8). 


CD9 has been found to be co-localized with FceRI, but there is only artificial evidence of modulation of degranulation by CD9 in RBL cells (9). Instead, CD9 has been demonstrated to act as the main interleukin 16 (IL-16) receptor of MC and to mediate MC chemotaxis towards an IL-16 gradient (10). 


A monoclonal antibody recognizing CD81 has been shown to inhibit mast cell degranulation after FceRI stimulation. As has been the case with the CD63 blocking antibody, the inhibitory effect was not mediated by inhibition of FceRI tyrosin phosphorylation, calcium influx, or leukotriene synthesis. Notably, the use of this antibody inhibited passive cutaneous anaphylaxis in a rat model (11).


The Tetraspanin CD151 seems to be expressed on most types of human mast cells and basophils, however there are no data showing a functional role of CD151 in these cells yet (6).


1. Draber P, Halova I, Levi-Schaffer F, Draberova L (2012) Front Immun 2:95.
2. Hemler ME (2005) Nat Rev Mol Cell Biol 6, 801-811.
3. Levy S, Shoham T (2005) Nature reviews Immunology 5, 136-148.
4. Berditchevski F (2001) J Cell Sci 114, 4143-4151.
5. Hennersdorf F, Florian S, Jakob A, Baumgartner K, Sonneck K, et al. (2005) Cell Res 15, 325-335.
6. Koberle M, Kaesler S, Kempf W, Wolbing F, Biedermann T (2012) Frontiers in immunology 3, 106.
7. Schafer T, Starkl P, Allard C, Wolf RM, Schweighoffer T (2010) Allergy 65, 1242-1255.
8. Kraft S, Fleming T, Billingsley JM, Lin SY, Jouvin MH, et al. (2005) J Exp Med 201, 385-396.
9. Higginbottom A, Wilkinson I, McCullough B, Lanza F, Azorsa DO, et al. (2000) Immunology 99, 546-552.
10. Qi JC, Wang J, Mandadi S, Tanaka K, Roufogalis BD, et al. (2006) Blood 107, 135-142.
11. Fleming TJ, Donnadieu E, Song CH, Laethem FV, Galli SJ, et al. (1997) J Exp Med 186, 1307-1314.

Table of Contents