CD4 and CD8

CD4 and CD8 are termed co-receptors because they bind to the same MHC molecule as does the TCR, and are often important for TCR triggering. The CD4 molecule is a chain of four Ig domains plus a membrane anchor and an intracellular portion. The CD4 first and second domains form a rigid rod because the last p strand of the first domain (strand G) is elongated to become the first p strand of the second domain (strand A).70-72 The N terminal domain is of the V type. The third and fourth domains repeat this arrangement to give a second rod, hinged to the first.71 The two N terminal domains engage the p chain of MHC class II28-73 (Fig. 1.5). The CD4-class II p2 domain interaction may be species specific.74

The CD8 molecule is a dimer,75,76 similar to TCR. The CDR loops of the V domains of CD8 engage the class I MHC molecule in the a3 domain.76 CD8 may be either an ap or aa dimer; the functions of these dimers may differ.77 The CD8-class I interaction is species specific, which could be relevant in xenotransplants.78

Diversity, Variability and Polymorphism

The MHC, TCR, and immunoglobulin products must exist in many forms to mediate specific antigen recognition. This requires diversity in the corresponding

Fig. 1.5. T cell receptor (TCR) engagement with the MHC. The TCR engages the upper surface of the MHC molecule. The co-receptors, CD4 for class II and CD8 for class I, also bind to the MHC, often triggering the TCR. The two N terminal domains of the CD4 engage the MHC class II. The structure of the TCR-MHC complex has never been solved. (Garboczi DN, Ghosh P, Utz U et al. Nature 1996; 384:134-141)

Fig. 1.5. T cell receptor (TCR) engagement with the MHC. The TCR engages the upper surface of the MHC molecule. The co-receptors, CD4 for class II and CD8 for class I, also bind to the MHC, often triggering the TCR. The two N terminal domains of the CD4 engage the MHC class II. The structure of the TCR-MHC complex has never been solved. (Garboczi DN, Ghosh P, Utz U et al. Nature 1996; 384:134-141)

genes, but the demands on MHC products are very different from those on TCRs and antibodies. MHC products are antigen presenting structures which must exist in many forms in the human population but few forms in any one individual. Thus MHC genes encode the proteins without random generation of diversity, but with enormous numbers of alleles in the population.

Antigen receptors (Ig and TCR) generate diversity randomly from a high number of genes encoding V regions of the L and H chains. These Ig genes rearrange in B cell precursors to randomly generate great diversity in selected sites, the CDRs. Thus, unlike the MHC alleles, the TCR and antibody genes combine germ line diversity with massive randomly generated somatic diversity to give each person an enormous repertoire of V region specificities by which antibody or TCRs can engage antigen. The potential repertoires of Ig and TCR chains is estimated at 106 to 109 specificities each.

Each Ag recognition structure involves combining two different chains (heavy chain with light chains in the Ig molecule, and a with p, or y with 6 in the TCR). The potential diversity created by combining such diverse molecules increases beyond 1010 for antibody and beyond 1015-18 for TCR ap and TCR y6.

In the case of MHC genes, the polymorphism is mainly confined to the bases encoding the amino acids lining the groove. In the TCR and Ig genes, the diversity is mostly confined to the regions encoding CDRs.

What Is Allorecognition?

When T cells of a recipient encounter allogeneic MHC, in the context of appropriate additional signals, stimulation of some of the recipient T-cell clones occurs. How allorecognition occurs in vivo is not clear. Small numbers of amino acid differences in the donor MHC can lead to strong responses. This could be because (1) they alter groove shape and thus determine peptide occupation of the groove; (2) they change the shape of the upper surface of the native molecule and change the interaction with the TCR; or (3) they make MHC peptides antigenic.

The donor MHC differences can be presented by either a direct or indirect pathway of presentation. "Direct" refers to recipient T cells recognizing donor MHC molecules on donor antigen presenting cells. Direct recognition could reflect recognition of a-helix differences affecting the contact sites for TCRs on the a-helices;80 or differences in the peptides in the groove.81,82

"Indirect" presentation of donor MHC requires recipient antigen presenting cells with peptides of donor MHC molecules in their grooves. Recent evidence has emphasized the importance of the indirect pathway, particularly since immunity and tolerance can be induced by peptide alone.83,84

The Potential Importance of Peptides of Donor MHC Antigens

Peptides from MHC class I proteins are prominent among peptides occupying the class I groove85-87 and peptides of class I and II and invariant chain are prominent in the class II groove of DR1.43,45,46,88 This has given rise to the possibility that a major component of -- across an MHC difference is due to recognition of MHC peptides in the donor (direct) or host (indirect) MHC grooves.

Indirect presentation of allogeneic donor MHC peptides in self MHC class II grooves (and possibly in class I grooves) by host antigen presenting cell (APC) must involve recognition of differences in amino acid sequences. Indirect presentation is a distinct possibility for triggering CD4 T cells, and could generate "help" for both T cell and antibody responses as well as inflammation akin to "delayed type hypersensitivity". However, graft injury by cytotoxic T cells must involve direct recognition.

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