Presentation of Nonpeptide Antigens

To this point the discussion has been limited to peptide antigens 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 dating back to the 1980s of T cell proliferation in the presence of nonprotein antigens derived from infectious agents. More recent reports indicate that T cells that express the 78 TCR (T-cell receptors are dimers of either ap or 78 chains) that react with glycolipid antigens derived from bacteria such as Mycobacterium tuberculosis. These nonprotein antigens are presented by members of the CD1 family of nonclassical class I molecules.

The CD1 family of molecules associates with p2-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, although 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 structure 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 professional 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 surface; 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 absence of foreign antigens, and self restriction can be demonstrated 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 presentation 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,

(a) HUMAN CHROMOSOME l

Gene name: CD1D

20 Kb

CD1A CD1C CD1B CD1E

MOUSE CHROMOSOME 3

Gene name: CD1D1 CD1D2

20 Kb

Gene name: CD1D1 CD1D2

Cd1d Structure

The CD1 family of genes and structure of a CD1d molecule. (a) The genes encoding the CD1 family of molecules in human (top) and mouse (bottom). The genes are separated into two groups based on sequence identity; CD1A, B, C, and E are group 1, CD1D genes are group 2. The products of the pink genes have been identified; products of grey genes have not yet been detected. (b) Comparison of the crystal structures of mouse non-classical CD1 and classical class I molecu le H-2kb. Note the differences in the antigen binding grooves. [Part (b) reprinted from Trends in Immunology (formerly Immunology Today), Vol. 19, S. A. Porcelli and R. L. Modlin, The CD1 family of lipid antigen presenting molecules, pp. 362-368, 1998, with permission from Elsevier Science.]

FIGURE 8-11

The CD1 family of genes and structure of a CD1d molecule. (a) The genes encoding the CD1 family of molecules in human (top) and mouse (bottom). The genes are separated into two groups based on sequence identity; CD1A, B, C, and E are group 1, CD1D genes are group 2. The products of the pink genes have been identified; products of grey genes have not yet been detected. (b) Comparison of the crystal structures of mouse non-classical CD1 and classical class I molecu le H-2kb. Note the differences in the antigen binding grooves. [Part (b) reprinted from Trends in Immunology (formerly Immunology Today), Vol. 19, S. A. Porcelli and R. L. Modlin, The CD1 family of lipid antigen presenting molecules, pp. 362-368, 1998, with permission from Elsevier Science.]

with CD 1a at the surface or in the recycling endocytic compartments and CD1b and CD1d in the lysomal compartments. Exactly how the CD1 pathway complements or intersects the better understood class I and class II pathways remains an open question. The T-cell types reactive to CD1 were first thought to be limited to T cells expressing the 78 TCR and lacking both CD4 and CD8, or T cells with a single TCR a chain, but recent reports indicate that a wider range of T-cell types will recognize CD1-presenting cells. Recent evidence indicates that natural killer T cells recognize CD1d molecules presenting au-tologous antigen. This may represent a mechanism for eliminating cells that are altered by stress, senescence, or neoplasia.

SUMMARY

■ T-cells recognize antigen displayed within the cleft of a self-MHC molecule on the membrane of a cell.

■ In general, CD4+ TH cells recognize antigen with class II MHC molecules on antigen-processing cells.

■ CD8+ TC cells recognize antigen with class I MHC molecules on target cells.

■ Complexes between antigenic peptides and MHC molecules are formed by degradation of a protein antigen in one of two different antigen-processing pathways.

■ Endogenous antigens are degraded into peptides within the cytosol by proteasomes and assemble with class I molecules in the RER.

■ Exogenous antigens are internalized and degraded within the acidic endocytic compartments and subsequently pair with class II molecules.

■ Peptide binding to class II molecules involves replacing a fragment of invariant chain in the binding cleft by a process catalyzed by nonclassic MHC molecule HLA-DM.

■ Presentation of nonpeptide (lipid and glycolipid) antigens derived from bacteria involves the class I—like CD1 molecules.

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