Lymphocyte antigen receptors: a common desgn?

Frits Koning

Specific antigen recognition in the immune system occurs through specialized membrane-bound recep- tors on lymphocytes: the 0~13 and y8 T-cell receptors (TCRs) and the B-cell receptors (BCRs) - the latter being the membrane-bound forms of IgM and IgD. Linked to the 'true' antigen-binding subunits of both the TCR and BCR complexes (i.e. the 0~13 or y8 TCR chains and IgM or IgD respectively) are a number of chains that, after specific antigen recog- nition, play a major role in signal transduction into the interior of the cell, leading to cellular activation.

Structure of the T-cell antigen receptor complex

The TCR-associated molecules are known as the CD3 complex (re- viewed in Ref. 1). The full TCR- CD3 complex comprises at least eight subunits (o~13ySee~ or ySy~ec~)* that all need to be pres- ent for stable, high-density cell sur- face expression. Although the struc- ture of the TCR-CD3 complex is still elusive and will probably re- main so for a number of years, a series of papers published recently 2-6 has shed some light on the structural requirements for proper cell surface expression of the TCR. Most of the TCR and CD3 chains are syn- thesized in vast excess and only a small percentage of these (less than 10%) actually reach the cell surface 2~. This is partly due to the rate limiting synthesis of the ~ pro- tein 7 which leads to the incomplete/ incorrect assembly of TCR-CD3

*TCR-CD3 complexes that contain a ~-q instead of a {{ dimer are also known. These complexes are not addressed here, although it is anticipated that the overall structure of ~{ and {~ dimers containing TCR-CD3 complexes will be very similar.

A recent flurry of papers has provided detailed information on the compo- nents of the T- and B-cell antigen re- ceptors. Although these individual elements, and the subunits they form, clearly differ, Frits Koning argues that the T- and B-cell receptor complexes may share a common underlying design.

complexes that are degraded intra- cellularly 2~. Two studies, one in humans 5 and one in mice 6, have ana- lysed subunit interactions in the TCR-CD3 complex. The results from these studies suggest that a number of stable subunit inter- actions can be discriminated that ap- pear to be very important for the assembly of the complex. Four 'building blocks' that may be used to generate a stable receptor complex could be defined: c~13 TCR or y~ TCR, ye CD3, 8e CD3 and ~ (Ref. 6 and Fig. l(a)).

A number of important predic- tions from this model are supported by more recent observations. Trans- genic mice that express human e CD3 can incorporate, in one given TCR-CD3 complex, both a mouse and a human ~ CD3 chain 8,9. This result supports the view that in the TCR-CD3 complex a minimum of two e CD3 chains must be present. It has also been shown that the trans- membrane regions of c~ TCR and 8 CD3 play a very important role in establishing a stable interaction be- tween these two chains. This obser- vation indicates that, in the TCR- CD3 complex, o~ TCR and 8 CD3 are adjacent 1°. Such a close association between y CD3 and 13 TCR had pre- viously been shown 11.

All the available evidence suggests that this model for the o~13 TCR- CD3 complex is also valid for the assembly of the chains in the y8 TCR-CD3 complex (Ref. 12 and Fig. l(b)). Thus, a picture is emerg- ing in which a 8e CD3 complex as- sociates with the o~(8) TCR chain and a ye CD3 complex associates with

© 1991, Elsevier Science Publishers Ltd, UK. 0167 -4919/91/$02.00

the 13(y) TCR chain. The y and CD3 chains appear to play an essen- tial role in dictating the specificity of these interactions, i.e. y CD3 with 13 TCR/y TCR and 8 CD3 with c~ TCR/8 TCR6,1°,IL As the y CD3 and 8 CD3 genes probably arose by a gene duplication event 13, it is poss- ible that, after this gene duplication, y CD3 and 8 CD3 gene products have evolved with distinct binding properties for the 13(-/) TCR and ~(8) TCR chains respectively. In this re- spect it is interesting to compare the structure of the TCR with that of the BCR.

Structure of the B-cell antigen receptor complex

Studies in humans and mice indi- cate that membrane-bound Ig is non- covalently associated with an 043 dimer 14-18. The mb-1 gene 19 prob- ably encodes for the ~ subunit of this Ig-associated c~13 dimer 17. The pro- tein sequence of the mb-1 gene prod- uct shows similarities with the CD3 proteins, including the presence of a negatively charged amino acid in the transmembrane region of the pro- tein 19. These charged amino acids may play a role in stabilizing inter- actions within the TCR and BCR complexes. At present there is no evidence for the existence of a ~ pro- tein in B cells, although low amounts of ~ mRNA appear to be present in B cells 2°. Considering the important role that the ~ chain plays in signal transduction in T cells 21, 22 and the recent observations that ~ and ~-like proteins are also found in associ- ation with the Fcy and Fce receptors respectively 2>2s, it may be a valid assumption that, with time, a pro- tein exhibiting ~-like properties will be identified in association with the e~13 BCR.

It is important to consider that, whereas in the TCR two distinct

Immunology Today 100 Vol 12 No. 4 1991

(b) ,

S-S

S-S

8

S-S

S-S

~" (c) ~

O/

S-S ~"

S-S H

C(J] TCR "/8 TCR BCR

Fig. 1. Model for the organization of the chains of (a) the c~ TCR, (b) the ~18 TCR and (c) the BCR in the membrane of lymphocytes. A view looking down on the plane of the membrane is shown. (a) is reproduced with permission from Ref. 6.

transmembrane chains are respon- sible for antigen recognition (cx and [3, ~/and 8), in the BCR two identical transmembrane H chains in combi- nation with two (nontransmem- brane) L chains serve this purpose. In the BCR complex, therefore, these transmembrane H chains are prob- ably linked to the 043 BCR dimers. These H chains may thus be con- sidered to be hornologues of the cxf3 and ~/8 TCR dimers. The need for two distinct CD3 chains (~ CD3 and 8 CD3) to mediate a specific inter- action between the individual TCR subunits and the ~,e CD3 and 8e CD3 complexes is then lacking in the BCR complex because it contains two identical H chain subunits. If it is postulated that the cd3 BCR dimer is

the structural homologue of the ~e CD3 and 8e CD3 dimers, two o~ BCR dimers in the BCR complex might be expected, each of them binding to an H chain subunit (Fig. 1(c)). As pointed out above, the existence (and position) of the X-like dimer in the BCR is still totally speculative.

Concluding remark t realize that the parallel drawn

between the structure of the TCR and the BCR is based on very little experimental evidence. It is, how- ever, tempting to make this com- parison since it seems quite logical that the TCR and the BCR are two evolutionary products derived from one common ancestor. It may, there-

fore, be reasonable to assume that the type of interactions that stabilize such receptors and allow cell surface expression and signal transduction have been conserved in evolution. Thus, although the TCR and BCR have very distinct functional proper- ties, they may nevertheless be built according to a common design.

The author would like to thank Peter van den Elsen, Chantal Rust, John Haanen, Jelle Thole and Tom Ottenhoff for critically reading the manuscript.

Frits Koning is at the Dept of Immunohematology and Bloodbank, University Hospital, Bldg 1, E3-Q, PO Box 9600, 2300 RC Leiden, The Netherlands.

References 1 Clevers, H., Alarcon, B., Wileman, T. and Terhorst, C. (1988) Annu. Rev. Immunol. 6, 629-662 2 Minami, Y., Weissman, A.M., Samelson, L.E. and Klausner, R.D. (1987) Proc. Natl Acad. Sci. USA 84, 2688-2692 3 Alarcon, B., Berkhout, B., Breitmeyer, J. and Terhorst, C. (1988) J. Biol. Cbem. 263, 2953-2961 4 Koning, F., Lew, A.M., Maloy, W.L. et al. (1988)]. Immunol. 140, 3126-3134 5 Bonifacino, J.S., Chen, C., Lippincott-Schwartz, J. et al. (1988) Proc. Natl Acad. Sci. USA 85, 6929-6933 6 Koning, F., Maloy, W.L. and Coligan, J.E. (1990) Eur. J. Immunol. 20, 299-305 7 Weissman, A.M., Frank, S.J., Orloff, D.G. etal. (1989) EMBOJ. 8, 3651-3656 8 De La Hera, A., Mfiller, U., Olsson,

C. et al. (1991) J. Exp. Meal. 173, 7-19 9 Blumberg, R.S., Ley, S., Sancho, J. et al. (1990) Proc. Natl Acad. Sci. USA 87, 7220-7224 10 Manolios, N., Bonifacino, J.S. and Klausner, R.D. (1990) Science 249, 274-277 11 Brenner, M.B., Trowbridge, I.S. and Strominger, J.L. (1985) Cell 40, 183-189 12 Neerven, J. van, Coligan, J.E. and Koning, F. (1990) Eur. J. Immunol. 20, 2105-2111 13 Krissanson, G.W., Owen, M.J., Verbi, W. and Crumpton, M.J. (1986) EMBO J. 5, 1799-1808 14 Hombach, J., Leclercq, L., Radbruch, A. et al. (1988) EMBO J. 7, 3451-3456 15 Campbell, K.S. and Cambier, J.C. (1990) EMBO J. 9, 441-448 16 Wienands, J., Hombach, J., Radbruch, A. et al. (1990) EMBO J. 9, 449-455

17 Hombach, J., Tsubata, T., Leclercq, L. et al. (1990) Nature 343,760-762 18 Noesel, C.J.M. van, Borst, J., Vries, E.F.R. de and Lier, R.A.W. van. (1990) Eur. J. Immunol. 20, 2789-2795 19 Sakaguchi, N., Kashiwamura, 8., Kimoto, M. et al. (1988) EMBO J. 7, 3457-3464 20 Weissman, A.M., Hou, D., Orloff, D.G. et al. (1988) Proc. NatI Acad. Sci. USA 85, 9709-9713 21 Samelson, L.E., Patel, M.D., Weissman, A.M. et al. (1986) Cell 46, 1083-1090 22 Mercep, M., Bonifacino, J.S., Garcia-Morales, P. et al. (1988) Science 242, 571-574 23 Anderson, P., Caligiuri, M., Ritz, J. and Schlossman, S.F. (1989) Nature 341,159-162 24 Lanier, L.L., Yu, G. and Phillips, J.H. (1990) Nature 342, 803-805 25 Blank, U, Ra, C., Miller, L. et al. (1989) Nature 337, 187-189

Immunology Today 101 Vol. 12 No. 4 1991