MHC and Immune Responsiveness

Early studies by B. Benacerraf in which guinea pigs were immunized with simple synthetic antigens were the first to show that the ability of an animal to mount an immune re sponse, as measured by the production of serum antibodies, is determined by its MHC haplotype. Later experiments by H. McDevitt, M. Sela, and their colleagues used congenic and recombinant congenic mouse strains to map the control of immune responsiveness to class II MHC genes. In early reports, the genes responsible for this phenotype were designated Ir or immune response genes, and for this reason mouse class II products are called IA and IE. We now know that the dependence of immune responsiveness on the class II MHC reflects the central role of class II MHC molecules in presenting antigen to TH cells.

Two explanations have been proposed to account for the variability in immune responsiveness observed among different haplotypes. According to the determinant-selection model, different class II MHC molecules differ in their ability to bind processed antigen. According to the alternative holes-in-the-repertoire model, T cells bearing receptors that recognize foreign antigens closely resembling self-antigens may be eliminated during thymic processing. Since the T-cell response to an antigen involves a trimolecular complex of the T cell's receptor, an antigenic peptide, and an MHC molecule (see Figure 3-8), both models may be correct. That is, the absence of an MHC molecule that can bind and present a given peptide, or the absence of T-cell receptors that can recognize a given peptide-MHC molecule complex, could result in the absence of immune responsiveness and so account for the observed relationship between

TABLE 7-3

Differential binding of peptides to mouse class II MHC molecules and correlation with MHC restriction

PERCENTAGE OF LABELED PEPTIDE BOUND TOf

TABLE 7-3

PERCENTAGE OF LABELED PEPTIDE BOUND TOf

Labeled peptide*

MHC restriction of responders1

IA'

IE'

IA*

IE*

Ovalbumin (323-339)

IAd

11.8

0.1

0.2

0.1

Influenza hemagglutinin (130-142)

IAd

18.9

0.6

7.1

0.3

Hen egg-white lysozyme (46-61)

IAk

0.0

0.0

35.2

0.5

Hen egg-white lysozyme (74-86)

IAk

2.0

2.3

2.9

1.7

Hen egg-white lysozyme (81 -96)

IEk

0.4

0.2

0.7

1 .1

Myoglobin (132-153)

IEd

0.8

6.3

0.5

0.7

Pigeon cytochrome c (88-104)

IEk

0.6

1.2

1.7

8.7

\ repressor (12-26)§

IAd + IEk

1.6

8.9

0.3

2.3

"Amino acid residues included in each peptide are indicated by the numbers in parentheses.

"'"Refers to class II molecule (IA or IE) and haplotype associated with a good response to the indicated peptides.

"Amino acid residues included in each peptide are indicated by the numbers in parentheses.

"'"Refers to class II molecule (IA or IE) and haplotype associated with a good response to the indicated peptides.

^Binding determined by equilibrium dialysis. Bold-faced values indicate binding was significantly greater (p < 0.05) than that of the other three class II molecules

§The k repressor is an exception to the rule that high binding correlates with the MHC restriction of high-responder strains. In this case, the Th cell specific for the k peptide—I E^ complex has been deleted; this is an example of the hole-in-the-repertoire mechanism.

SOURCE: Adapted from S. Buus et al., 1987, Science 235:1353.

MHC haplotype and immune responsiveness to exogenous antigens.

According to the determinant-selection model, the MHC polymorphism within a species will generate a diversity of binding specificities, and thus different patterns of responsiveness to antigens. If this model is correct, then class II MHC molecules from mouse strains that respond to a particular antigen and those that do not should show differential binding of that antigen. Table 7-3 presents data on the binding of various radiolabeled peptides to class II IA and IE molecules with the H-2d or H-2^ haplotype. Each of the listed peptides binds significantly to only one of the IA or IE molecules. Furthermore, in all but one case, the haplotype of the class II molecule showing the highest affinity for a particular peptide is the same as the haplotype of responder strains for that peptide, as the determinant-selection model predicts.

The single exception to the general pattern in Table 7-3 (residues 12-26 of the X repressor protein) gives evidence that the influence on immune responsiveness can also be caused by absence of functional T cells (holes-in-the-reper-toire model) capable of recognizing a given antigen-MHC molecule complex. The X repressor peptide binds best in vitro to IEd, yet the MHC restriction for response to this pep tide is known to be associated not with IEd but instead with IAd and IE^. This suggests that T cells recognizing this repressor peptide in association with IEd may have been eliminated by negative selection in the thymus, leaving a hole in the T-cell repertoire.

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