- Email: [email protected]
Receptor editing during affinity maturation
COMMENT I M M U N O L O G Y T O D AY
letters Receptor editing during affinity maturation As recently discussed1, B cells can rearrange their immunoglobulin genes, even though they express a functional antibody molecule. In immature B cells this contributes to the maintenance of tolerance2,3. However, the adaptive advantage for mature B cells, which can undergo V(D)J recombination in vivo following antigenic stimulation4Ð7, is unclear. Ig rearrangement is unlikely to be involved in editing autoreactive B cells produced by somatic hypermutation, as the process is turned off by interaction with high affinity antigens8. An alternative is that receptor editing provides an additional means of introducing diversity in B cells during the process of affinity maturation. However, this raises the question of what advantage there is in having such an additional process of receptor diversification. We suggest that receptor editing offers the ability to escape from local optima on an affinity landscape. A highly simplified affinity landscape9 is shown in Fig. 1. All possible antigen-binding sites are shown on the xaxis, with the most similar adjacent to each other (for simplicity the landscape in Fig. 1
has one parameter or dimension to describe the antigen-binding sites Ð modelling suggests that between five and eight dimensions are needed in Euclidean shape spaces to match the experimental data10). The affinity of the binding sites for a nominal antigen is shown on the y-axis. If we take a particular antibody that has been selected during the primary immune response (A), then point mutations allow the immune system to explore the local area around A by making small alterations in the shape of the antigen-binding site. If any of these mutations produces a binding site with higher affinity then they are selected for. Thus, by a series of small steps (shown in red), the antibody climbs the hill until it reaches a maximum (A9). Because mutations with a lower affinity are lost, the antibody cannot go down the hill. As a result, in a highly rugged landscape, an antibody undergoing somatic point mutation might become stuck at a local optimum (A9), unable to increase its affinity further. Receptor editing allows an antibody to take large leaps through the landscape (green). In most cases this will land the antibody in a locale where the affinity is lower (B). However, occasionally the leap will generate an antibody on the side of a higher hill (C); the antibody can then use point mu-
tations to climb to the top of that hill (C9). Inhibition of recombinase activity by high affinity interactions ensures that this process is turned off when it is not needed8. Therefore, affinity maturation without receptor editing would have difficulty in producing very high affinity antibodies. The importance of receptor editing will be dependent on the size of the primary B-cell repertoire. Animals with a large B-cell repertoire will cover the affinity landscape more efficiently than those with a small repertoire, and so the immune response (taken as a whole) is less likely to be trapped on relatively low, local optima. In conclusion, point mutation is good for exploring local regions of the affinity landscape, whereas receptor editing may rescue immune responses stuck on relatively low, local optima. Thus receptor editing and point mutation might play complementary roles in affinity maturation of antibodies. Andrew J.T. George David Gray Dept of Immunology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK W12 0NN. References 01 Rajewsky, K. (1998) Nature 394, 624Ð625 02 Gay, D., Saunders, T., Camper, S. and Weigert, M. (1993) J. Exp. Med. 177, 999Ð1008
C'
03 Tiegs, S.L., Russell, D.M. and Nemazee, D. (1993) J. Exp. Med. 177, 1009Ð1020
Affinity
04 Han, S., Dillon, S.R., Zheng, B. et al. (1997) Science 278, 301Ð305
C
A'
05 Han, S., Zheng, B., Schatz, D.G., Spanopoulou, E. and Kelsoe, G. (1996) Science 274, 2094Ð2097 06 Papavasiliou, F., Casellas, R., Suh, H. et al.
A
(1997) Science 278, 298Ð301
B
07 Hikida, M., Mori, M., Takai, T. et al. (1996) Science 274, 2092Ð2094 08 Hertz, M., Kouskoff, V., Nakamura, T. and Nemazee, D. (1998) Nature 394, 292Ð295
Antigen-binding sites
09 Perelson, A.S. and Oster, G.F. (1979) J. Theor. Biol. 81, 645Ð670 10 Smith, D.J., Forrest, S., Hightower, R.R. and
Fig. 1. A schematic representation of the shape space for antigen-binding sites. See text for detailed description.
A P R I L 196
1 9 9 9 Vo l . 2 0
No.4
Perelson, A.S. (1997) J. Theor. Biol. 189, 141Ð150
letters Receptor editing during affinity maturation As recently discussed1, B cells can rearrange their immunoglobulin genes, even though they express a functional antibody molecule. In immature B cells this contributes to the maintenance of tolerance2,3. However, the adaptive advantage for mature B cells, which can undergo V(D)J recombination in vivo following antigenic stimulation4Ð7, is unclear. Ig rearrangement is unlikely to be involved in editing autoreactive B cells produced by somatic hypermutation, as the process is turned off by interaction with high affinity antigens8. An alternative is that receptor editing provides an additional means of introducing diversity in B cells during the process of affinity maturation. However, this raises the question of what advantage there is in having such an additional process of receptor diversification. We suggest that receptor editing offers the ability to escape from local optima on an affinity landscape. A highly simplified affinity landscape9 is shown in Fig. 1. All possible antigen-binding sites are shown on the xaxis, with the most similar adjacent to each other (for simplicity the landscape in Fig. 1
has one parameter or dimension to describe the antigen-binding sites Ð modelling suggests that between five and eight dimensions are needed in Euclidean shape spaces to match the experimental data10). The affinity of the binding sites for a nominal antigen is shown on the y-axis. If we take a particular antibody that has been selected during the primary immune response (A), then point mutations allow the immune system to explore the local area around A by making small alterations in the shape of the antigen-binding site. If any of these mutations produces a binding site with higher affinity then they are selected for. Thus, by a series of small steps (shown in red), the antibody climbs the hill until it reaches a maximum (A9). Because mutations with a lower affinity are lost, the antibody cannot go down the hill. As a result, in a highly rugged landscape, an antibody undergoing somatic point mutation might become stuck at a local optimum (A9), unable to increase its affinity further. Receptor editing allows an antibody to take large leaps through the landscape (green). In most cases this will land the antibody in a locale where the affinity is lower (B). However, occasionally the leap will generate an antibody on the side of a higher hill (C); the antibody can then use point mu-
tations to climb to the top of that hill (C9). Inhibition of recombinase activity by high affinity interactions ensures that this process is turned off when it is not needed8. Therefore, affinity maturation without receptor editing would have difficulty in producing very high affinity antibodies. The importance of receptor editing will be dependent on the size of the primary B-cell repertoire. Animals with a large B-cell repertoire will cover the affinity landscape more efficiently than those with a small repertoire, and so the immune response (taken as a whole) is less likely to be trapped on relatively low, local optima. In conclusion, point mutation is good for exploring local regions of the affinity landscape, whereas receptor editing may rescue immune responses stuck on relatively low, local optima. Thus receptor editing and point mutation might play complementary roles in affinity maturation of antibodies. Andrew J.T. George David Gray Dept of Immunology, Division of Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK W12 0NN. References 01 Rajewsky, K. (1998) Nature 394, 624Ð625 02 Gay, D., Saunders, T., Camper, S. and Weigert, M. (1993) J. Exp. Med. 177, 999Ð1008
C'
03 Tiegs, S.L., Russell, D.M. and Nemazee, D. (1993) J. Exp. Med. 177, 1009Ð1020
Affinity
04 Han, S., Dillon, S.R., Zheng, B. et al. (1997) Science 278, 301Ð305
C
A'
05 Han, S., Zheng, B., Schatz, D.G., Spanopoulou, E. and Kelsoe, G. (1996) Science 274, 2094Ð2097 06 Papavasiliou, F., Casellas, R., Suh, H. et al.
A
(1997) Science 278, 298Ð301
B
07 Hikida, M., Mori, M., Takai, T. et al. (1996) Science 274, 2092Ð2094 08 Hertz, M., Kouskoff, V., Nakamura, T. and Nemazee, D. (1998) Nature 394, 292Ð295
Antigen-binding sites
09 Perelson, A.S. and Oster, G.F. (1979) J. Theor. Biol. 81, 645Ð670 10 Smith, D.J., Forrest, S., Hightower, R.R. and
Fig. 1. A schematic representation of the shape space for antigen-binding sites. See text for detailed description.
A P R I L 196
1 9 9 9 Vo l . 2 0
No.4
Perelson, A.S. (1997) J. Theor. Biol. 189, 141Ð150