trends Cell adhesion in the immune system Charles R. Mackay and Beat A. Imhof Leukocyte adhesion to the endo- thelium is a multi-step process ~'-'. Studies in vitro and in vivo by Timothy Springer (Boston), Eugene Butcher (Stanford) and Steven Shaw (Bethesda) indicate that the initial attachment of leukocytes to a vessel wall under flow conditions is me- diated by selectins, including P- selectin or E-selectin on eado- thelium, or L-selectin on leukocytes (see Fig. 1). A feature of this ad- hesion is the 'rolling' of the leuko- cyte. A signalling event then causes the activation of integrins on leuko- cytes, by altering the conformation of the e×tracellular binding do- main of these molecules. This arrests the rolling process, and leads to firm attachment of the leukocyte through, for instance, the adhesion molecules LFA-1 and ICAM-1 or VLA-4 and VCiLM-1. The leukocyte then changes shape and migrates through the endo- thelium. Thus the specificity of leukocyte binding for various endo- thelia relies on sequential and com- binatorial processes, rather than a single binding event 1~'18. A significant development was pre-sented by Shaw (see pages 111-114 of this issue). He argued that inflammatory cytokines in vivo would be rapidly washed away, so a mechanism should exist to cap- ture and immobilize certain cytokines on endothelium, where they can mediate ~ctivation and in- duction of adhesioa. The cytokine studied by Shaw was macrophage inflammatory protein- 1l] (MIP-1~), a member of the chemokine family. MIP-I[3 was particularly effective in promoting the adhesion of CD8 ~ T cells, through binding to VCAM-1. Different chemokines may operate for other subsets, and so regulate the type of leukocyte entering a tis- sue, particularly during the course of an inflammatory response. This Cell adhesion molecules have an important role I9 play in m,,,y facets of the immune system. At a recent meeting* their role in leukocyte migration, inflam- mation, cancer metastasis and lymphocyte development was discussed. may explain the differential mi- gration of T-cell subsets to various tissues ~, as well as the striking specificity of certain leukocytes for inflamed tissue, such as eosinophil binding to nasal endothelium in hay fever (Butcher). The molecular mechanism for the immobilization of MIP-11] on endothelium was through its binding to surface proteoglycans, including CD44 (Shaw). The differential expression of various proteoglycans on differ- ent endothelia may also be a factor in determining the type of cytokine that is immobilized. The latest developments, as well as earlier data, of lymphocyte attachment to the endothelium are summarized in Table 1. The mucosal ad&essin, termed MadCAM-1 and recognized by mAb MECA-367, has been cloned and sequenced (Briskin and Butcher). MadCAM-1 is expressed on the high endothelial venules (HEV) of Peyer's Patches and mesenteric lymph nodes, and anti- bodies to it block the binding of gut-associated lymphocytes to these endothelia4. It is comprised of four domains: an ICAM-1/VCAM-1- like domain; another VCAM-I-like domain; a mucin-like sequence; and a domain with homology to the immunoglobulin Cot2. The ICAM/ VCAM Ig domains suggested an interaction with integrins, and this proved to be the case, since anti- bodies to 137 and o~4 inhibited the binding of lymphocytes to purified *The EMBO workshop on cell ad- hesion in the immune system was held at the Basel Institute for Immunology November 1992. O 1993, Else~,er Science Publishers Ltd, UK. 0167-5699/93/$06.00 MadCAM-1. Other in vivo and in vitro blocking studies indicate that the o~4137integrin is responsible for gut-homing (Irv Weissman, Stanfordh however this integrin, like o~4~1, can also bind so VCAM-1, which is expressed on inflamed endothelium but is absent from the gut. Sirpa Jalkanen (Turku) stated that there was still room for new adhesion molecules on the endo- thelium, such as vascular adhesion protein-1 (VAP-1). She also pre- sented some preliminary work sug- gesting a possible ligand for CD44, which appears to be distinct from any of the other binding factors for CD44. Dietmar Vestweber (Freiburg) showed that in addition to ICAM-1, VCAM-1 and E-selectin, there were additional molecules on endothelium that could be upregulated bv inflammatory cyto- kines (TNF), such as P-selectin and an as yet uncharacterized molecule. Steven Rosen tSan Franci~cnl nr~- • - ....... t 1 .--o- sented his and Larry Lasky's most recent work on a ligand for L- selectin s, which they have termed GIyCAM-1. It is a mucin-like gly- coprotein, 70% carbohydrate by mass. The ligand a:tivity of GIyCAM-1 for L-selectin is criti- cally dependent on sialylation, fucosylation and sulfation of O- linked chains. However Butcher suggested that selectin binding car- bohydrates involved lymphocyte interaction s of which GlyCAM is one attached to a number of differ- ent proteins. A few of the presentations dealt with lymphocyte homing in vwo. Thomas Issekutz (Halifax) pre- sented data showing that LFA-1 and VLA-4 facilitated T-cell mi- gration to inflamed tissue. Other studies by Issekutz using rats were consistent with those using mice (Alf Hamman, Hamburg) in show- ing that ~t4 integrin determines Immunology Today 99 Vol 14 No. 3 1993