Immunology Today, vol. 7, No. 3, 1986
-rt it ,,s
The evolution of MHC class II genes The known class II molecules encoded in the major histocompatibility complex (MHC) genes consist of two chains, ot and 13, joined on the cell surface by noncovalent bonds. Each chain consists of two extracellular domains (eL1, ~2, 131, and 132), a connecting peptide, a transmembrane region, and a cytoplasmic tail. In the human, the chains are encoded in at least four closely linked gene clusters, DP, DO/DZ, DQ, and DR, presumably arranged in this order on chromosome 6, where the DP cluster is the closest to the centromere and the DR cluster the furthest away. Each cluster contains at least one o~ and one 13 gene. According to our knowledge at present, the DP cluster contains four genes, DP62, DPc,2, DP~I and DP,~I arranged in this order. The DO/DZ cluster may contain at least two genes, DO# and DZ~ (it has not as yet been agreed which of these two designations should be used). The DQ cluster contains four genes, DQI~2, DQ,~2, DQ~I and DQ~I, presumably arranged in this order. The DR cluster contains three 13 genes and one o~ gene: DRI31, DRy2, DRr33and DRy. The DQ and DR c~and 13 genes are characteristically oriented in a head-tohead' fashion so that the transcription of a 13 gene starts at its centromeric end, whereas the transcription of an o~gene starts at its telomeric end; the DP o~and 13genes are oriented in a tail-to-tail fashion 1. There are seven class II genes known in the mouse: AI33, AI32, AI31, A~, E#, Eb2, E~ and E63, arranged in this order on chromosome 17, where the AI33 is the closest to the centromere and the El33 gene the furthest away. The AI33 is homologous to the human genes in the DP cluster but appears to be nonfunctional. The A62 gene is homologous to the DO gene whereas the A 1 and As genes are homologous to the human DQ genes; only the A#I and A~ genes are known to be functional. The E62, EI~I, and E~ genes are homologous to the human DR genes but, again, only E#I and E~ are known to be functional. The homology and the functional status of the El33 gene are not known. The composition and organization of class II genes in other species are also not known 1. Although short N-terminal amino acid sequences have been determined for a number of class II molecules, only two molecules (human DR~ and DR~ chains) have been sequenced in their entirety2,3. However, for over 50 chains (o~ or 13) complete or almost complete amino acid sequences have been deduced from the nucleotide sequences of the corresponding genes. Fifty-two of these sequences are depicted in the centre-page diagram of this issue. The chains and the respective source of information are listed in Table 1. (For technical reasons, the chain and allomorph designations are written in the diagram on a single line; hence, for example, H-2Aeb represents H-2A b, H-2A13d rep78
Felipe Figueroa and Jan Klein
resents H-2Ad~, and so on. The human sequences in each cluster have been numbered but the numbers signify sequences, and not loci or alleles; for the most part it is not known in which locus of a given cluster a given sequence is encoded.) The colour code in the centre-page diagram reflects postulated evolutionary relationships between the depicted sequences. The light blue indicates either invariant residues shared by all chains or 'ancestral' residues which are presumed to have been present at one particular position before the diversification process placed other residues in that position in certain chains. In the latter case, light blue residues can be thought of as 'carry-overs' from the ancient sequences. (We list the e and 13 sequences separately; since there is very little homology between them at the amino acid sequence level, it was not possible to align the e with the 13 chains. Therefore, the sharing indicated by the colour code always refers to either c¢ or 13 chains, but not to both simultaneously.) At some positions, two ancestral residues occur (i.e., residues shared by chains that belong to two or more not directly related clusters). In such cases, one set of residues is indicated by light blue and the other by the colour orange. Pink/light blue/purple indicates residues characterizing the H-2A-HLA-DQ cluster. These can either be shared by the H-2A and HLA-DQ chains (pink), be H-2A-specific (dark blue), or be HLA-DQ-specific (purple). The green colour indicates residues characterizing the H-2E and HLA-DR clusters. These, again, can either be shared by the H-2E and HLA-DR chains (light green), be H-2E-specific (dark green), or be HLADR-specific (intermediate green). The DP-A~3specific residues are indicated by the yellow colour (here, because there is only one A#3 sequence, the same colour indicates either DP-A63-shared or DPspecific residues). The crimson colour indicates sequences shared by m o u s e AI3 2 and rat A62 sequences, at least some of which are presumably also shared with the human DO~ sequence (not available to us at the time of writing). Note that some of the mouse and rat AI3 2 sequences are shared with the A#I-DQ,-DP, cluster and are absent in the E~-DR~ cluster, while others are shared with the Ep-DR# cluster and are absent in the A#I-DQ6-DP, cluster (indicated by the colour orange). There are virtually no mouse/rat A~2 sequences shared with the A#3-DP# cluster. This distribution of shared residues suggests that the A~IDQ#, A,2-DO,, and E~-DR~ clusters evolved from a single set of ancestral genes which existed after the ancestral genes of the A~3-DP~ cluster split off from Max Planckinstitut for Biologie,AbteilungImmungenetik,Correns- the common stem of the evolutionary tree. In the o~ sequences, the situation is somewhat straBe42, 7400T(Jbingen1,FederalRepublicof Germany O 1986, ElsevierScience PublishersB.V, Amsterdam 0167 4919/86/$0200
For technical reasonswe are unable to include the centre page diagram in this edition. See the March issue of Immunology Todayfor the centre pacjes.
Immunology Today, vol. 7, No. 3, 1986
reviews-
Table 1 Listof genesfromwhichthe aminoacidsequencesin the centre-pagediagramwerededuced
Gene
Reference
Gene
Reference
Gene
Reference
H-2A~ H-2A~ H-2A~ HLA-DQI~(1) HLA-DQ, (2) HLA-DQ~(3) HLA-DQ~(4) HLA-DQp(5) RT1.A~ H-2A#2 RT1.A~2 H-2E~ H-2E~ H-2Ep H-2E~ H-2E~ H-2E~~7 H-2E~2 HLA-DR#(1)
4, 5 5, 6 5
HLA-DRp(2) HLA-DRp(3) HLA-DR~(4) HLA-DR~(5) HLA-DR#(6) H-2Ap3 HLA-DPp(1) HLA-DP~(2) HLA-DP#(3) HLA-DP, (4) HLA-DPp(5) H-2Ab H-2Ad H-2Af H-2Au H-2Aq H-2A~ H-2A S, H-2A~
23 23 24 2 25 26 27 28 28 29, 30 31 32 32 32 32 32 33 34 34
RT1.E, HLA-DQ~(1) HLA-DQ~(2) HLA-DQ~(3) HLA-DQ~(4) HLA-DQ~(5) HLA-DQ~(6) RT1.A~ H-2Ed H-2Ek HLA-DR, (1) HLA-DR~(2) HLA-DR~(3) HLA-DR~(4) HLA-DR~(5) HLA-DZ, HLA-DP~(1) HLA-DP~,(2)
35 36 37 6 38 39 39 40 41,42 43 44 45 46 47 48 49 39 50
7 8 9 10 11 12 13 14 15, 16
17 18 19 20 PJones,pers.commun. 21
22
simpler than in the 13sequences, mainly because of lower variability and a lower number of the.encoding genes. Here, the colour code is the same as that of the 13 sequences. Worth mentioning is that the DZ, chain shows a considerable homology with the A,-DQ, cluster sequences. There are residues at several positions that are shared by DZ~, A~ and DQ,, but are lacking in all the other sequences. Only at three positions are there residues that are shared by DZ~, E~ and DR, and are absent in the other c~ chains. This observation may indicate that the separation of the E,-DR, genes from the common stem of the tree may have occurred later than the separation of the A~-DQ~ genes.
On the basis of these observations, we propose a scheme of class II gene evolution which is depicted in Fig. 1. According to this scheme, the ancestral class II gene duplicated very early on in the evolution and the two resulting elements became the ancestors of the cx and 13 genes. The duplication may have occurred twice, the first time giving rise to DP ancestral genes and the second time to DQ-DZ-DR ancestral genes. The former duplication arranged the 13-cxgenes in the tail-to-tail configuration; the latter duplication arranged them in the head-to-head configuration. From then on, further evolution occurred by the duplication of the 13-c~ modules and deletion of some genes from these
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Fig.1. Postulatedevolutionof classII MHCgenes.Each rectanglerepresentsa single gene. Crossedrectangles indicatea deletionof a gene;arrowsindicatedirectionof transcriptionfrom the 5' to the 3' end,in relationto the centromere.(FromJ. Klein NaturalHistoryof the Major Hist0compatibilityComplex,Wiley,New York, 1986.)
I
I
79
Immunology Today, voL 7, No. 3, 1986
-reviews modules. In the primate line, the DP 13-~ module duplicated once and produced the four contemporary DP genes. The DZ module either did not duplicate at all or the duplication was followed by a deletion of one module. The D Q module duplicated once and produced the four contemporary D Q genes, and the DR module duplicated twice but the duplication was followed by the deletion of two c~ genes. In the rodent line, the DP module may have duplicated (there is evidence for multiple DP-tike genes in the mole-rat, Spalax e h r e n b e r g i : D. Nizetic~ e t a / . , unpublished) but during the evolution of the Muridae, most of the duplicated genes were lost so that in the mouse, only one 13 gene remained. The DZ module may not have duplicated and, moreover, may have lost its c~ gene. The D Q module may have duplicated (again, there is evidence for multiple DQ-like genes in the mole-rat: D. Nizetic~ e t a l . , unpublished) but in the mouse, all the duplicated genes except one 13 and one ~ had been lost by deletions. The DR module may have duplicated once (or more than once) but one of the ~ genes was subsequently lost. The origin of the El33 gene is uncertain at the present time and we could not place it into the proposed scheme because the sequence of this gene was not available to us. This scheme differs from the one we proposed for the evolution of class I genes sl. To explain the data available for the class I genes and proteins, we h a d to postulate that at least the functional genes arose from a common cluster by independent events in the primate and rodent lines. Because of this mode of evolution, the different genes in the t w o lines appear equidistant from one another. By contrast, genes in each of the class II clusters have a common origin in both the primate and rodent evolutionary lines. Hence, in the evolution of class II genes, there was a common module from which all the DP-like genes arose, in both the human and the mouse; a common module from which all the DO/DZ-like genes arose; and so on. It is therefore somewhat easier to follow the evolution of the class II than that of the class I genes. As in the case of class I genes, it is possible to construct evolutionary trees of codons in such a way that the trees match the scheme in Fig. 1. and the postulated changes consist of single nucleotide substitutions. It therefore appears that the class II genes have evolved primarily in an orthodox way, by mutation and selection. References
80
1 M~ller, G. (ed.) (1985) 'Molecular Geneticsof ClassI and II MHC Antigens', Immunological Reviews Vols 84 and 85, Munksgaard, Copenhagen 2 Kratzin, H., Yang, C.-Y., GOtz, H. etal. (1981). HoppeSeyler's Z. Physiol. Chem. 362, 1665-1669 3 Yang, C.Y., Kratzin, H., G6tZ, H. etal. (1982)Hoppe-Seyler's Z. PhysioL Chem. 363,671-676 4 Larhammar, D., Hammerling, U., Denaro, M. etaL (1983) Cell 34, 179-188 5 Choi, E., Mclntyre, K., Germain, R.N. etaL (1983)Science 221,283-286 6 Malissen, M., Hunkapiller,T. and Hood, L. (1983) Science 221,750-754
7 Bos_%J.Mand Strominger, J.L. (1984) Proc. NatlAcad. Sci, USA 81, 5199-5203 8 Schenning, L., Larhammar, D., Bill, P. etal. (1984) EMBOJ. 3, 447-452 9 Larhammar, D., Hyldig-Nielsen,J.J., Servenius,B. etal. (1983) Proc. NatlAcad. Sci. USA 80, 7313-7317 10 Larhammar, D., Schenning, L., Gustafsson, K. etaL (1982) Proc. Natl. Acad. Sci. USA 79, 3687-3691 11 G6tz, H., Kratzin, H., Thinnes, F.P.et al. (1983) HoppeSeyler's Z. PhysioL Chem. 364, 749-755 12 Eccles,S.J. and McMaster, W.R. (1985) Transplant. Proc. 17, 1801-1804 13 Larhammar, D., Hammerling, U., Rask,L. etaL (1985)J. Biol. Chem. 260, 1411-1417 14 Scholler,J. and Lernmark, ~,. (1985) lmmunogenetics 22, 601-608 15 Denaro, M., Hammerling, U., Rask, L. etaL (1984)EMBOJ. 3, 2029-2032 16 Widera, G. and Flavell,R.A. (1984) EMBO J. 3, 1221-1225 17 Saito, H., Maki, R.A., Clayton, L.K. etaL (1983) Proc Natl Acad. Sci. USA 80, 5520-5524 18 Mengle-Gaw, L. and McDevitt, H.O. (1983) Proc NatlAcad. Sci, USA 80, 7621-7630 19 Mengie-Gaw, L. and McDevitt, H.O. (1983)Proc. NatlAcad. Sci. USA 82, 2910 2914 20 Mengle-Gaw, L. and McDevitt, H.O. (1984)in Regulation of the Immune System, Cantor, H., Chess, L. and Serrcarz, E. eds), pp. 2945. Alan R. Liss,New York 21 Denaro, M., Gustafsson, K., Larhammar, D. etal. (1985) Immunogenetics21, 613 616 22 Long, E.O.,Wake, C.T., Gorski, J. etaL (1983) EMBOJ. 2, 389-394 23 Gustafsson, K., Wiman, K., Emmoth, E. etal. (1984)EMBO J. 3, 1655-1661 24 Bell,J.l., Estess,P., John, T. St. et al. (1985) Proc. NatlAcad. Sci. USA 82, 3405-3409 25 Larhammar, D., Servenius,B., Rask, L. etal. (1985) Proc. Natl Acad. 5ci. USA 82, 1475-1479 26 Wldera, G. and Flavell,R.A. (1985) Proc. NatlAcad. Sci. USA 82, 5500-5504 27 Kelly,A. and Trowsdale, J. (1985) Nucleic Acids Res. 13, 1607-1621 28 Gustafsson, K., Emmoth, E., Widmark, E. etaL (1984) Nature (London) 309, 76 78 29 Roux-Dosseto,M., Auffray, C., Lillie,J. etal. (1983) Proc. NatlAcad. Sci. USA 80, 6036 6040 30 Kappes, D.J., Arnot, D., Okada, K etal. (1984)EMBOJ. 3, 2985-2993 31 Long, E.O., Gorski, J. and Mach, B. (1984) Nature (London) 310, 233-235 32 Benoist, C.O., Mathis, D.J., Kanter, M.R. etaL (1983) Cell 34, 169-177 33 Benoist, C.O., Mathis, D.J., Kanter, M.R. etal. (1983) Proc Natl Acad. Sci, USA 80, 534-538 34 Landais, D., Mattes, H., Benoist, C. etal. (1985) Proc. Natl Acad. Sci. USA 82, 2930-2934 35 Holowachuk, E. (1985)Imnmunogenetics, 22,665 672 36 Auffray, C., Korman, A.J., Roux-Dosseto,M. etaL (1982) Proc. Natl Acad. 5ci. USA 79, 6337-6341 37 Chang, H.-C., Moriuchi, T. and Silver,J. (1983) Nature (London) 305, 813-815 38 Moriuchi, J., Moriuchi, T., and Silver,J. (1985) Proc IVatl Acad. Sci. USA 82, 3420 3424 39 Auffray, C., Lillie,J.W., Arnot, D. etaL (1984) Nature (London) 308, 327-333 40 Wallis, A.E. and McMaster, W.R. (1984) Immunogenetics 19, 53-62 41 Hyldig-Nielsen,J.J., Schenning, L., Hammerling, U. etal. (1983) IVucleicAcids Res. 11, 5055 5071 42 McNicholas,J., Steinrnetz,M., Hunkapiller, T. etaL (1982) Science 218, 1229-1232 43 Mathis, D.J., Benoist, C.O., Williams, V.E. etaL (1983) Cell
Immunology Today, voL 7, No. 3, 1986
reviews 32,745-754 44 Korman,A.J., Auffray, C., Schambooek,A. etaL (1982) Proc. Natl Acad. Sci. USA 79, 6013-6017 45 Chang, H.-C., Moriuchi, T. and Silver,J. (1983)Nature (London) 305, 813-815 46 Das,H.K., Lawrence, S.K.and Weissman, S.M. (1983) Proc. NatlAcad. Sci. USA 80, 3543-3547 41 Larhammar, D., Gustafsson,K., Claesson,L. etaL (1982)
-
Ceil 30, 153-161
48 Lee,J.S.,Trowsdale,J., Travers,P.J.etal. (1982) Nature
(London) 299, 750-752 49 Trowsdale,J., Young, J.A.T., Kelly,A.P. etaL (1985) ImmunoL Rev. 85, 5-43 50 Servenius,B., Gustafsson,K., Widmark, E. etal. (1984) EMBOJ. 3, 3209-3214 51 Klein,J. and Figueroa, F. (1985)lmmunol. Today6, 41-44
To his many theoretical contributions to immunology, the late Richard Gershon added, in 1974, the concept of 'contrasuppression'. He saw the need, within a network of immunoregulatory mechanisms, for a means of overcoming the active suppression of an immune response that was itself capable of regulation and did not simply increase the effectiveness of available T-cell help. In the past few years, Gershon's collaborators and others have given life to the theory with a series of studies demonstrating the existence of T-cell subsets and factors with contrasuppressive activity.
Contrasuppression in the mouse Contrasuppressor T cells interfere with suppression in a manner which is distinct from T cell help or the augmentation of T cell help. The contrasuppressor effector cell, which resembles helper T cells in that it bears the Lyt 1 cell-surface antigen, can be distinguished from helper cells by virtue of a number of other characteristics (Table 1), which are discussed in more detail below. Contrasuppression exerts a positive influence on the immune response in the presence of active suppression. In the absence of helper cells and/or suppressor cells, contrasuppressor cells appear to do nothing. Animals in which contrasuppression (but not help) has been induced display no immunity, but upon subsequent analysis can be found to be resistant to the effects of suppression oh the induction of immunity ~. In practice, such animals, while not being immune, are refractory to the induction of tolerance. This is a simple idea: contrasuppression produces a resistance to suppression without, itself, inducing immune responses. However, it may be difficult to understand what purpose such an activity may serve for the immune system. A clue to one purpose for contrasuppression can be found in the 'paradox' of oral tolerance. When antigen is ingested, it is often possible to observe a stage in which systemic exposure to the same antigen fails to induce an immune response (due to the presence of suppressor T cells) while, at the same time, the gut associated lymphoid tissues (GALT) are found to be actively sensitized 2. There is a clear rationale for such a state: both food antigens and pathogens may enter the system via the gut; the immune
Departmentof Immunology, Universityof Alberta, Edmonton,Alberta, Canada; and Departmentof Experimentaland ClinicalImmunology, CopernicusSchoolof Medicine, Cracow,Poland
DouglasR. GreenandW. Ptak system must control the pathogens, but systemic responses (say, to food antigens) could be disastrous. Therefore, the responses are localized to the gut, while systemic responses are actively suppressed. The Peyer's patches of the GALT contain a population of T contrasuppressor inducer cells 3. Upon ingestion of antigen, potent antigen-specific contrasuppressor cells may be found in the Peyer's patches 4 while antigen specific suppressor T (Ts) cells are found in the spleen 5 . Thus, contrasuppresTable 1 ContrasuppressorTcellsare not helpercells.Thistable lists phenotypicandfunctionalcharacteristicsof helperT cellsand contrasuppressorTcells.Mostof theseare discussedin the text Characteristic
HelperTcell
Lyt 1+ Lyt2 L3T4+ I-J+ Viciavillosalectin B-celldeprivedmice
Yes Yes Yes No Nonadherent Present
Inducesimmunity Producesresistance to suppression Antigenspecific Antigen recognized in the contextof classII MHC molecules
Contrasuppressor effectorTcell Yes Yes Yes/No* Yes Adherent Absent
Yes No
No Yes
Yes Yes
Yes No
*depending on systemunderstudy
(~ 1986, ElsevierSciencePublishers 8.V., Amsterdam 0 1 6 7 -
4919/86/$02.00
81
-rt it ,,s
The evolution of MHC class II genes The known class II molecules encoded in the major histocompatibility complex (MHC) genes consist of two chains, ot and 13, joined on the cell surface by noncovalent bonds. Each chain consists of two extracellular domains (eL1, ~2, 131, and 132), a connecting peptide, a transmembrane region, and a cytoplasmic tail. In the human, the chains are encoded in at least four closely linked gene clusters, DP, DO/DZ, DQ, and DR, presumably arranged in this order on chromosome 6, where the DP cluster is the closest to the centromere and the DR cluster the furthest away. Each cluster contains at least one o~ and one 13 gene. According to our knowledge at present, the DP cluster contains four genes, DP62, DPc,2, DP~I and DP,~I arranged in this order. The DO/DZ cluster may contain at least two genes, DO# and DZ~ (it has not as yet been agreed which of these two designations should be used). The DQ cluster contains four genes, DQI~2, DQ,~2, DQ~I and DQ~I, presumably arranged in this order. The DR cluster contains three 13 genes and one o~ gene: DRI31, DRy2, DRr33and DRy. The DQ and DR c~and 13 genes are characteristically oriented in a head-tohead' fashion so that the transcription of a 13 gene starts at its centromeric end, whereas the transcription of an o~gene starts at its telomeric end; the DP o~and 13genes are oriented in a tail-to-tail fashion 1. There are seven class II genes known in the mouse: AI33, AI32, AI31, A~, E#, Eb2, E~ and E63, arranged in this order on chromosome 17, where the AI33 is the closest to the centromere and the El33 gene the furthest away. The AI33 is homologous to the human genes in the DP cluster but appears to be nonfunctional. The A62 gene is homologous to the DO gene whereas the A 1 and As genes are homologous to the human DQ genes; only the A#I and A~ genes are known to be functional. The E62, EI~I, and E~ genes are homologous to the human DR genes but, again, only E#I and E~ are known to be functional. The homology and the functional status of the El33 gene are not known. The composition and organization of class II genes in other species are also not known 1. Although short N-terminal amino acid sequences have been determined for a number of class II molecules, only two molecules (human DR~ and DR~ chains) have been sequenced in their entirety2,3. However, for over 50 chains (o~ or 13) complete or almost complete amino acid sequences have been deduced from the nucleotide sequences of the corresponding genes. Fifty-two of these sequences are depicted in the centre-page diagram of this issue. The chains and the respective source of information are listed in Table 1. (For technical reasons, the chain and allomorph designations are written in the diagram on a single line; hence, for example, H-2Aeb represents H-2A b, H-2A13d rep78
Felipe Figueroa and Jan Klein
resents H-2Ad~, and so on. The human sequences in each cluster have been numbered but the numbers signify sequences, and not loci or alleles; for the most part it is not known in which locus of a given cluster a given sequence is encoded.) The colour code in the centre-page diagram reflects postulated evolutionary relationships between the depicted sequences. The light blue indicates either invariant residues shared by all chains or 'ancestral' residues which are presumed to have been present at one particular position before the diversification process placed other residues in that position in certain chains. In the latter case, light blue residues can be thought of as 'carry-overs' from the ancient sequences. (We list the e and 13 sequences separately; since there is very little homology between them at the amino acid sequence level, it was not possible to align the e with the 13 chains. Therefore, the sharing indicated by the colour code always refers to either c¢ or 13 chains, but not to both simultaneously.) At some positions, two ancestral residues occur (i.e., residues shared by chains that belong to two or more not directly related clusters). In such cases, one set of residues is indicated by light blue and the other by the colour orange. Pink/light blue/purple indicates residues characterizing the H-2A-HLA-DQ cluster. These can either be shared by the H-2A and HLA-DQ chains (pink), be H-2A-specific (dark blue), or be HLA-DQ-specific (purple). The green colour indicates residues characterizing the H-2E and HLA-DR clusters. These, again, can either be shared by the H-2E and HLA-DR chains (light green), be H-2E-specific (dark green), or be HLADR-specific (intermediate green). The DP-A~3specific residues are indicated by the yellow colour (here, because there is only one A#3 sequence, the same colour indicates either DP-A63-shared or DPspecific residues). The crimson colour indicates sequences shared by m o u s e AI3 2 and rat A62 sequences, at least some of which are presumably also shared with the human DO~ sequence (not available to us at the time of writing). Note that some of the mouse and rat AI3 2 sequences are shared with the A#I-DQ,-DP, cluster and are absent in the E~-DR~ cluster, while others are shared with the Ep-DR# cluster and are absent in the A#I-DQ6-DP, cluster (indicated by the colour orange). There are virtually no mouse/rat A~2 sequences shared with the A#3-DP# cluster. This distribution of shared residues suggests that the A~IDQ#, A,2-DO,, and E~-DR~ clusters evolved from a single set of ancestral genes which existed after the ancestral genes of the A~3-DP~ cluster split off from Max Planckinstitut for Biologie,AbteilungImmungenetik,Correns- the common stem of the evolutionary tree. In the o~ sequences, the situation is somewhat straBe42, 7400T(Jbingen1,FederalRepublicof Germany O 1986, ElsevierScience PublishersB.V, Amsterdam 0167 4919/86/$0200
For technical reasonswe are unable to include the centre page diagram in this edition. See the March issue of Immunology Todayfor the centre pacjes.
Immunology Today, vol. 7, No. 3, 1986
reviews-
Table 1 Listof genesfromwhichthe aminoacidsequencesin the centre-pagediagramwerededuced
Gene
Reference
Gene
Reference
Gene
Reference
H-2A~ H-2A~ H-2A~ HLA-DQI~(1) HLA-DQ, (2) HLA-DQ~(3) HLA-DQ~(4) HLA-DQp(5) RT1.A~ H-2A#2 RT1.A~2 H-2E~ H-2E~ H-2Ep H-2E~ H-2E~ H-2E~~7 H-2E~2 HLA-DR#(1)
4, 5 5, 6 5
HLA-DRp(2) HLA-DRp(3) HLA-DR~(4) HLA-DR~(5) HLA-DR#(6) H-2Ap3 HLA-DPp(1) HLA-DP~(2) HLA-DP#(3) HLA-DP, (4) HLA-DPp(5) H-2Ab H-2Ad H-2Af H-2Au H-2Aq H-2A~ H-2A S, H-2A~
23 23 24 2 25 26 27 28 28 29, 30 31 32 32 32 32 32 33 34 34
RT1.E, HLA-DQ~(1) HLA-DQ~(2) HLA-DQ~(3) HLA-DQ~(4) HLA-DQ~(5) HLA-DQ~(6) RT1.A~ H-2Ed H-2Ek HLA-DR, (1) HLA-DR~(2) HLA-DR~(3) HLA-DR~(4) HLA-DR~(5) HLA-DZ, HLA-DP~(1) HLA-DP~,(2)
35 36 37 6 38 39 39 40 41,42 43 44 45 46 47 48 49 39 50
7 8 9 10 11 12 13 14 15, 16
17 18 19 20 PJones,pers.commun. 21
22
simpler than in the 13sequences, mainly because of lower variability and a lower number of the.encoding genes. Here, the colour code is the same as that of the 13 sequences. Worth mentioning is that the DZ, chain shows a considerable homology with the A,-DQ, cluster sequences. There are residues at several positions that are shared by DZ~, A~ and DQ,, but are lacking in all the other sequences. Only at three positions are there residues that are shared by DZ~, E~ and DR, and are absent in the other c~ chains. This observation may indicate that the separation of the E,-DR, genes from the common stem of the tree may have occurred later than the separation of the A~-DQ~ genes.
On the basis of these observations, we propose a scheme of class II gene evolution which is depicted in Fig. 1. According to this scheme, the ancestral class II gene duplicated very early on in the evolution and the two resulting elements became the ancestors of the cx and 13 genes. The duplication may have occurred twice, the first time giving rise to DP ancestral genes and the second time to DQ-DZ-DR ancestral genes. The former duplication arranged the 13-cxgenes in the tail-to-tail configuration; the latter duplication arranged them in the head-to-head configuration. From then on, further evolution occurred by the duplication of the 13-c~ modules and deletion of some genes from these
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I
I
Fig.1. Postulatedevolutionof classII MHCgenes.Each rectanglerepresentsa single gene. Crossedrectangles indicatea deletionof a gene;arrowsindicatedirectionof transcriptionfrom the 5' to the 3' end,in relationto the centromere.(FromJ. Klein NaturalHistoryof the Major Hist0compatibilityComplex,Wiley,New York, 1986.)
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Immunology Today, voL 7, No. 3, 1986
-reviews modules. In the primate line, the DP 13-~ module duplicated once and produced the four contemporary DP genes. The DZ module either did not duplicate at all or the duplication was followed by a deletion of one module. The D Q module duplicated once and produced the four contemporary D Q genes, and the DR module duplicated twice but the duplication was followed by the deletion of two c~ genes. In the rodent line, the DP module may have duplicated (there is evidence for multiple DP-tike genes in the mole-rat, Spalax e h r e n b e r g i : D. Nizetic~ e t a / . , unpublished) but during the evolution of the Muridae, most of the duplicated genes were lost so that in the mouse, only one 13 gene remained. The DZ module may not have duplicated and, moreover, may have lost its c~ gene. The D Q module may have duplicated (again, there is evidence for multiple DQ-like genes in the mole-rat: D. Nizetic~ e t a l . , unpublished) but in the mouse, all the duplicated genes except one 13 and one ~ had been lost by deletions. The DR module may have duplicated once (or more than once) but one of the ~ genes was subsequently lost. The origin of the El33 gene is uncertain at the present time and we could not place it into the proposed scheme because the sequence of this gene was not available to us. This scheme differs from the one we proposed for the evolution of class I genes sl. To explain the data available for the class I genes and proteins, we h a d to postulate that at least the functional genes arose from a common cluster by independent events in the primate and rodent lines. Because of this mode of evolution, the different genes in the t w o lines appear equidistant from one another. By contrast, genes in each of the class II clusters have a common origin in both the primate and rodent evolutionary lines. Hence, in the evolution of class II genes, there was a common module from which all the DP-like genes arose, in both the human and the mouse; a common module from which all the DO/DZ-like genes arose; and so on. It is therefore somewhat easier to follow the evolution of the class II than that of the class I genes. As in the case of class I genes, it is possible to construct evolutionary trees of codons in such a way that the trees match the scheme in Fig. 1. and the postulated changes consist of single nucleotide substitutions. It therefore appears that the class II genes have evolved primarily in an orthodox way, by mutation and selection. References
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7 Bos_%J.Mand Strominger, J.L. (1984) Proc. NatlAcad. Sci, USA 81, 5199-5203 8 Schenning, L., Larhammar, D., Bill, P. etal. (1984) EMBOJ. 3, 447-452 9 Larhammar, D., Hyldig-Nielsen,J.J., Servenius,B. etal. (1983) Proc. NatlAcad. Sci. USA 80, 7313-7317 10 Larhammar, D., Schenning, L., Gustafsson, K. etaL (1982) Proc. Natl. Acad. Sci. USA 79, 3687-3691 11 G6tz, H., Kratzin, H., Thinnes, F.P.et al. (1983) HoppeSeyler's Z. PhysioL Chem. 364, 749-755 12 Eccles,S.J. and McMaster, W.R. (1985) Transplant. Proc. 17, 1801-1804 13 Larhammar, D., Hammerling, U., Rask,L. etaL (1985)J. Biol. Chem. 260, 1411-1417 14 Scholler,J. and Lernmark, ~,. (1985) lmmunogenetics 22, 601-608 15 Denaro, M., Hammerling, U., Rask, L. etaL (1984)EMBOJ. 3, 2029-2032 16 Widera, G. and Flavell,R.A. (1984) EMBO J. 3, 1221-1225 17 Saito, H., Maki, R.A., Clayton, L.K. etaL (1983) Proc Natl Acad. Sci. USA 80, 5520-5524 18 Mengle-Gaw, L. and McDevitt, H.O. (1983) Proc NatlAcad. Sci, USA 80, 7621-7630 19 Mengie-Gaw, L. and McDevitt, H.O. (1983)Proc. NatlAcad. Sci. USA 82, 2910 2914 20 Mengle-Gaw, L. and McDevitt, H.O. (1984)in Regulation of the Immune System, Cantor, H., Chess, L. and Serrcarz, E. eds), pp. 2945. Alan R. Liss,New York 21 Denaro, M., Gustafsson, K., Larhammar, D. etal. (1985) Immunogenetics21, 613 616 22 Long, E.O.,Wake, C.T., Gorski, J. etaL (1983) EMBOJ. 2, 389-394 23 Gustafsson, K., Wiman, K., Emmoth, E. etal. (1984)EMBO J. 3, 1655-1661 24 Bell,J.l., Estess,P., John, T. St. et al. (1985) Proc. NatlAcad. Sci. USA 82, 3405-3409 25 Larhammar, D., Servenius,B., Rask, L. etal. (1985) Proc. Natl Acad. 5ci. USA 82, 1475-1479 26 Wldera, G. and Flavell,R.A. (1985) Proc. NatlAcad. Sci. USA 82, 5500-5504 27 Kelly,A. and Trowsdale, J. (1985) Nucleic Acids Res. 13, 1607-1621 28 Gustafsson, K., Emmoth, E., Widmark, E. etaL (1984) Nature (London) 309, 76 78 29 Roux-Dosseto,M., Auffray, C., Lillie,J. etal. (1983) Proc. NatlAcad. Sci. USA 80, 6036 6040 30 Kappes, D.J., Arnot, D., Okada, K etal. (1984)EMBOJ. 3, 2985-2993 31 Long, E.O., Gorski, J. and Mach, B. (1984) Nature (London) 310, 233-235 32 Benoist, C.O., Mathis, D.J., Kanter, M.R. etaL (1983) Cell 34, 169-177 33 Benoist, C.O., Mathis, D.J., Kanter, M.R. etal. (1983) Proc Natl Acad. Sci, USA 80, 534-538 34 Landais, D., Mattes, H., Benoist, C. etal. (1985) Proc. Natl Acad. Sci. USA 82, 2930-2934 35 Holowachuk, E. (1985)Imnmunogenetics, 22,665 672 36 Auffray, C., Korman, A.J., Roux-Dosseto,M. etaL (1982) Proc. Natl Acad. 5ci. USA 79, 6337-6341 37 Chang, H.-C., Moriuchi, T. and Silver,J. (1983) Nature (London) 305, 813-815 38 Moriuchi, J., Moriuchi, T., and Silver,J. (1985) Proc IVatl Acad. Sci. USA 82, 3420 3424 39 Auffray, C., Lillie,J.W., Arnot, D. etaL (1984) Nature (London) 308, 327-333 40 Wallis, A.E. and McMaster, W.R. (1984) Immunogenetics 19, 53-62 41 Hyldig-Nielsen,J.J., Schenning, L., Hammerling, U. etal. (1983) IVucleicAcids Res. 11, 5055 5071 42 McNicholas,J., Steinrnetz,M., Hunkapiller, T. etaL (1982) Science 218, 1229-1232 43 Mathis, D.J., Benoist, C.O., Williams, V.E. etaL (1983) Cell
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To his many theoretical contributions to immunology, the late Richard Gershon added, in 1974, the concept of 'contrasuppression'. He saw the need, within a network of immunoregulatory mechanisms, for a means of overcoming the active suppression of an immune response that was itself capable of regulation and did not simply increase the effectiveness of available T-cell help. In the past few years, Gershon's collaborators and others have given life to the theory with a series of studies demonstrating the existence of T-cell subsets and factors with contrasuppressive activity.
Contrasuppression in the mouse Contrasuppressor T cells interfere with suppression in a manner which is distinct from T cell help or the augmentation of T cell help. The contrasuppressor effector cell, which resembles helper T cells in that it bears the Lyt 1 cell-surface antigen, can be distinguished from helper cells by virtue of a number of other characteristics (Table 1), which are discussed in more detail below. Contrasuppression exerts a positive influence on the immune response in the presence of active suppression. In the absence of helper cells and/or suppressor cells, contrasuppressor cells appear to do nothing. Animals in which contrasuppression (but not help) has been induced display no immunity, but upon subsequent analysis can be found to be resistant to the effects of suppression oh the induction of immunity ~. In practice, such animals, while not being immune, are refractory to the induction of tolerance. This is a simple idea: contrasuppression produces a resistance to suppression without, itself, inducing immune responses. However, it may be difficult to understand what purpose such an activity may serve for the immune system. A clue to one purpose for contrasuppression can be found in the 'paradox' of oral tolerance. When antigen is ingested, it is often possible to observe a stage in which systemic exposure to the same antigen fails to induce an immune response (due to the presence of suppressor T cells) while, at the same time, the gut associated lymphoid tissues (GALT) are found to be actively sensitized 2. There is a clear rationale for such a state: both food antigens and pathogens may enter the system via the gut; the immune
Departmentof Immunology, Universityof Alberta, Edmonton,Alberta, Canada; and Departmentof Experimentaland ClinicalImmunology, CopernicusSchoolof Medicine, Cracow,Poland
DouglasR. GreenandW. Ptak system must control the pathogens, but systemic responses (say, to food antigens) could be disastrous. Therefore, the responses are localized to the gut, while systemic responses are actively suppressed. The Peyer's patches of the GALT contain a population of T contrasuppressor inducer cells 3. Upon ingestion of antigen, potent antigen-specific contrasuppressor cells may be found in the Peyer's patches 4 while antigen specific suppressor T (Ts) cells are found in the spleen 5 . Thus, contrasuppresTable 1 ContrasuppressorTcellsare not helpercells.Thistable lists phenotypicandfunctionalcharacteristicsof helperT cellsand contrasuppressorTcells.Mostof theseare discussedin the text Characteristic
HelperTcell
Lyt 1+ Lyt2 L3T4+ I-J+ Viciavillosalectin B-celldeprivedmice
Yes Yes Yes No Nonadherent Present
Inducesimmunity Producesresistance to suppression Antigenspecific Antigen recognized in the contextof classII MHC molecules
Contrasuppressor effectorTcell Yes Yes Yes/No* Yes Adherent Absent
Yes No
No Yes
Yes Yes
Yes No
*depending on systemunderstudy
(~ 1986, ElsevierSciencePublishers 8.V., Amsterdam 0 1 6 7 -
4919/86/$02.00
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