8536d_ch08_185-199 8/2/02 10:08 AM Page 196 mac79 Mac 79: 45_Bwppldsby et al./ Immunology Se 196 PART I1 Generation of B-Cell and T-Cell Response that HLA-DM is widely conserved among mammalian recognized by the immune system, and there are reports dat species. Like other class II MHC molecules, HLA-DM is a ing back to the 1980s of T cell proliferation in the presence of molecules, HLA-DM is not polymorphic and is not ex- cent reports indicate that T cells that express the y8 TCR (T- pressed at the cell membrane but is found predominantly cell receptors are dimers of either aB or y8 chains)that react within the endosomal compartment. The DMa and DMB with glycolipid antigens derived from bacteria such as My- genes are located near the TAP and LMP genes in the MHC cobacterium tuberculosis. These nonprotein antigens are pre- omplex of humans and DM is expressed in cells that express sented by members of the CDI family of nonclassical class I classical class ll molecules The reaction between HLA-DM and the class lI Clip The CDI family of molecules associates with B2-mi- complex facilitating exchange of CLIP for another peptide is croglobulin and has general structural similarity to class I impaired in the presence of HLA-DO, which binds to HLA- MHC molecules. There are five genes encoding human CDI DM and lessens the efficiency of the exchange reaction. HLA- molecules(CDIA-E, encoding the gene products CDla-d DO, like HLA-DM, is a nonclassical and nonpolymorphic with no product yet identified for E). These genes are located lass II molecule that is also found in the MHC of other not within the MHC but on chromosome 1(Figure 8-11a species. HLA-DO differs from HLA-DM in that it is ex- The genes are classified into two groups based on sequence pressed only by B cells and the thymus, and unlike other class homology Group I includes CDIA, B, C, and E, CDID is in Il molecules, its expression is not induced by IFN-y. An ad- group 2. All mammalian species studied have CDI genes, al ditional difference is that the genes encoding the a and the p though the number varies. Rodents have only group 2 CDI hains of HLA-DO are not adjacent in the MHC as are all genes, the counterpart of human CDID, whereas rabbits, like other class Il o and B pairs(see Fig 7-15) humans, have five genes, including both group l and 2 types An HLA-DR3 molecule associated with CLIP was isolated Sequence identity of CDI with classical class I molecules is from a cell line that did not express HLA-DM and was there- considerably lower than the identity of the class I molecules fore defective in antigen processing. Superimposing the with each other. Comparison of the three-dimensional struc- structure of hla-dr3-cliP on another dr molecule ture of the mouse didi with the class i mhc molecule h- bound to antigenic peptide reveals that CLIP binds to class ll 2k shows that the antigen-binding groove of the CDld in the same stable manner as the antigenic peptide( figure 8- molecules is deeper and more voluminous than that of the 10b). The discovery of this stable complex in a cell with de- classical class I molecule(Fig 8-11b) fective HLA-DM supports the argument that HLA-DM Expression of CDl molecules varies according to subset; required for the replacement of CLIP. CDIDI genes are expressed mainly in nonprofessional APCs Although it certainly modulates the activity of HLA-DM, and on certain B-cell subsets. The mouse CDldI is more the precise role of HLA-DO remains obscure. One possibility widely distributed and found on T cells, B cells, dendritic is that it acts in the selection of peptides bound to class II cells, hepatocytes, and some epithelial cells. The CDIA, B, MHC molecules in B cells DO occurs in complex with DM and Genes are expressed on immature thymocytes and pro- in these cells and this association continues in the endosomal fessional APCs, mainly those of the dendritic type. CDIC compartments. Conditions of higher acidity weaken the as- gene expression is seen on B cells, whereas the CDIA and B sociation of DM/DO and increase the possibility of antigenic products are not. CDI genes can be induced by exposure to peptide binding despite the presence of DO. Such a pH-de- certain cytokines such as GM-CSF or IL-3. The intracellular endent interaction could lead to preferential selection of trafficking patterns of the CDI molecules differ; for example class Il-bound peptides from lysosomal compartments in b CDla is found mostly in early endosomes or on the cell sur cells as compared with other APCs face: CDlb and cDld localize to late endosomes: and CDIc with class I MHC molecules, peptide binding is required is found throughout the endocytic system. to maintain the structure and stability of class II MHC mole- Certain CDI molecules are recognized by T cells in the ab- cules. Once a peptide has bound, the peptide-class II complex sence of foreign antigens, and self restriction can be demon- is transported to the plasma membrane, where the neutral pH strated in these reactions. Examination of antigens presented ppears to enable the complex to assume a compact, stable by CDI molecules revealed them to be lipid components form Peptide is bound so strongly in this compact form that it (mycolic acid )of the M. tuberculosis cell wall. Further studies is difficult to replace a class Il-bound peptide on the mem- of CDl presentation indicated that a glycolipid(lipoarabino- brane with another peptide at physiologic conditions. mannan)from Mycobacterium leprae could also be presented by these molecules. The data concerning CDI antigen pre- sentation point out the existence of a third pathway for the Presentation of Nonpeptide Antigens processing of antigens, a pathway with distinct intracellular steps that do not involve the molecules found to facilitate To this point the discussion has been limited to peptide anti- class I antigen processing. For example, CDI molecules are gens and their presentation by classical class I and II MHC able to process antigen in TAP-deficient cells. Recent data molecules. It is well known that nonprotein antigens also are indicate that the CDla and lb molecules traffic differently,that HLA-DM is widely conserved among mammalian species. Like other class II MHC molecules, HLA-DM is a heterodimer of  and  chains. However, unlike other class II molecules, HLA-DM is not polymorphic and is not ex￾pressed at the cell membrane but is found predominantly within the endosomal compartment. The DM and DM genes are located near the TAP and LMP genes in the MHC complex of humans and DM is expressed in cells that express classical class II molecules. The reaction between HLA-DM and the class II CLIP complex facilitating exchange of CLIP for another peptide is impaired in the presence of HLA-DO, which binds to HLA￾DM and lessens the efficiency of the exchange reaction. HLA￾DO, like HLA-DM, is a nonclassical and nonpolymorphic class II molecule that is also found in the MHC of other species. HLA-DO differs from HLA-DM in that it is ex￾pressed only by B cells and the thymus, and unlike other class II molecules, its expression is not induced by IFN-. An ad￾ditional difference is that the genes encoding the  and the  chains of HLA-DO are not adjacent in the MHC as are all other class II  and  pairs (see Fig 7-15). An HLA-DR3 molecule associated with CLIP was isolated from a cell line that did not express HLA-DM and was there￾fore defective in antigen processing. Superimposing the structure of HLA-DR3–CLIP on another DR molecule bound to antigenic peptide reveals that CLIP binds to class II in the same stable manner as the antigenic peptide (Figure 8- 10b). The discovery of this stable complex in a cell with de￾fective HLA-DM supports the argument that HLA-DM is required for the replacement of CLIP. Although it certainly modulates the activity of HLA-DM, the precise role of HLA-DO remains obscure. One possibility is that it acts in the selection of peptides bound to class II MHC molecules in B cells. DO occurs in complex with DM in these cells and this association continues in the endosomal compartments. Conditions of higher acidity weaken the as￾sociation of DM/DO and increase the possibility of antigenic peptide binding despite the presence of DO. Such a pH-de￾pendent interaction could lead to preferential selection of class II-bound peptides from lysosomal compartments in B cells as compared with other APCs. As with class I MHC molecules, peptide binding is required to maintain the structure and stability of class II MHC mole￾cules. Once a peptide has bound, the peptide–class II complex is transported to the plasma membrane, where the neutral pH appears to enable the complex to assume a compact, stable form. Peptide is bound so strongly in this compact form that it is difficult to replace a class II–bound peptide on the mem￾brane with another peptide at physiologic conditions. Presentation of Nonpeptide Antigens To this point the discussion has been limited to peptide anti￾gens and their presentation by classical class I and II MHC molecules. It is well known that nonprotein antigens also are recognized by the immune system, and there are reports dat￾ing back to the 1980s of T cell proliferation in the presence of nonprotein antigens derived from infectious agents. More re￾cent reports indicate that T cells that express the  TCR (T￾cell receptors are dimers of either  or  chains) that react with glycolipid antigens derived from bacteria such as My￾cobacterium tuberculosis. These nonprotein antigens are pre￾sented by members of the CD1 family of nonclassical class I molecules. The CD1 family of molecules associates with 2-mi￾croglobulin and has general structural similarity to class I MHC molecules. There are five genes encoding human CD1 molecules (CD1A-E, encoding the gene products CD1a-d, with no product yet identified for E). These genes are located not within the MHC but on chromosome 1 (Figure 8-11a). The genes are classified into two groups based on sequence homology. Group 1 includes CD1A, B, C, and E; CD1D is in group 2. All mammalian species studied have CD1 genes, al￾though the number varies. Rodents have only group 2 CD1 genes, the counterpart of human CD1D, whereas rabbits, like humans, have five genes, including both group 1 and 2 types. Sequence identity of CD1 with classical class I molecules is considerably lower than the identity of the class I molecules with each other. Comparison of the three-dimensional struc￾ture of the mouse CD1d1 with the class I MHC molecule H- 2kb shows that the antigen-binding groove of the CD1d1 molecules is deeper and more voluminous than that of the classical class I molecule (Fig 8-11b). Expression of CD1 molecules varies according to subset; CD1D1 genes are expressed mainly in nonprofessional APCs and on certain B-cell subsets. The mouse CD1d1 is more widely distributed and found on T cells, B cells, dendritic cells, hepatocytes, and some epithelial cells. The CD1A, B, and C genes are expressed on immature thymocytes and pro￾fessional APCs, mainly those of the dendritic type. CD1C gene expression is seen on B cells, whereas the CD1A and B products are not. CD1 genes can be induced by exposure to certain cytokines such as GM-CSF or IL-3. The intracellular trafficking patterns of the CD1 molecules differ; for example, CD1a is found mostly in early endosomes or on the cell sur￾face; CD1b and CD1d localize to late endosomes; and CD1c is found throughout the endocytic system. Certain CD1 molecules are recognized by T cells in the ab￾sence of foreign antigens, and self restriction can be demon￾strated in these reactions. Examination of antigens presented by CD1 molecules revealed them to be lipid components (mycolic acid) of the M. tuberculosis cell wall. Further studies of CD1 presentation indicated that a glycolipid (lipoarabino￾mannan) from Mycobacterium leprae could also be presented by these molecules. The data concerning CD1 antigen pre￾sentation point out the existence of a third pathway for the processing of antigens, a pathway with distinct intracellular steps that do not involve the molecules found to facilitate class I antigen processing. For example, CD1 molecules are able to process antigen in TAP-deficient cells. Recent data indicate that the CD1a and 1b molecules traffic differently, 196 PART II Generation of B-Cell and T-Cell Responses 8536d_ch08_185-199 8/2/02 10:08 AM Page 196 mac79 Mac 79:45_BW:Goldsby et al. / Immunology 5e: