T H Hansen

Antigen Presenting Function of Macrophages

The immune response to many natural and synthetic protein antigens has been shown to be controlled by genes (Ir) linked to the major histocompatibility complex (MHC). Animals possessing Ir genes can elicit a strong immune response against a particular antigen. Animals lacking the specific Ir gene are deficient in either humoral or cellular immunity. Ir genes were shown to control only T cell mediated responses to T-dependent antigens1. Antibody production was affected secondarily as a result of this impaired T cell — B cell interaction. Responses to T-independent antigens which activate B lymphoctes directly are not under Ir gene control.

Ia Oligosaccharide Structure and Its Relation to Differential Recognition of Ia

A considerable amount of interest in glycosylation of Ia and DR protein molecules has developed recently. This is a trend that can be explained in two ways, one practical, and the other exploratory.

Antibody and T Cell Recognition of Select Ia Determinants Using the I-A Mutant B6.C-H-2 bm12

Recognition of self Ia antigens is necessary for interactions between T cells, B cells, macrophages and certain soluble factors culminating in immune responsiveness to foreign antigens. Recognition of allogeneic Ia antigen has been purported to mimic self-recognition of Ia plus foreign antigen. A new approach to study the recognition of Ia is now possible due to the availability of the I-A mutant B6.C-H-2bm12. Since bm12 mice have a gain-loss mutation in the gene encoding the Ab beta polypeptide, responses between bm12 and B6 recognize select Ia determinants corresponding to either the gain or loss specificities resulting from the mutation. Also resultant from this mutation are known differences between mutant and wild-type as detected by mixed lymphocyte responses (1) and Ir gene functions (2,3). In this report we investigate the recognition of Ia antigens in the humoral and T-cell responses between bm12 and B6 mice. This approach not only allows for comparisons between the antibody and T-cell responses to select Ia determinants, but may also give important insights into the recognition of self Ia antigens.

T-Cells Recognize IA Conformation in the Interaction with Antigen Presenting Cells

The presentation of soluble antigens by antigen presenting cell (APC) to T-cells requires that the antigen be recognized in the context of an Ia determinant (Shevach and Rosenthal, 1973). Although the T cell antigen receptor has been identified and sequenced (Hedrick et al., 1984; Fink et al., 1986), the nature of the ligand that triggers the T cells remains unclear. The early experiments of Lin et al. (1981) and Michaelides et al. (1983) using the IA mutant strain of mouse B6.C-H-2 bml 2 (bm1 2) demonstrated that limited alteration of the Ia molecule concomitantly led to changes in the response pattern of T-cells to soluble antigens. Specifically, it was shown that bml 2 lost immune responsiveness to the antigens beef insulin and H-Y while their responses to other antigens remained normal when compared to the wild type C57BL/6. Besides providing convincing evidence equating Ia to the Ir gene product, these experiments also suggest that there are multiple funcitonal domains (Beck et al., 1983) on the Ia molecule that by some unknown mechanisms determine responsiveness to certain antigens. Indeed, this conclusion is consistent with other studies using a variety of approaches such as monoclonal antibody blocking (Frelinger et al., 1984), site-directed mutagenesis (Cohen et al., 1986), in vitro selection of variant APC lines (Glimcher et al., 1983b) and inhibition of specific antigen response with structurally related co-polymers (Benacerraf and Rock, 1984). More recently, Babbitt and coworkers (1985) using biochemical methods demonstrated a weak but measurable physical association between a hen egg lysozyme antigenic fragment and purified Ia molecules. This association was demonstrated for Ia derived from responder strains but not that from non-responder strains. In another analysis, Ashwell and Schwartz (1986) also provided arguments that antigen and Ia physically interacted to form a ternary complex recognizable by the T-cell antigen receptor.

Do T Cells Recognize the Same Ia Epitopes on Antigen Presenting Cells and on B Cells

While it is generally believed that antigen presenting cells exhibit Ir gene functions, there has been a long debate as to whether Ir genes are also expressed at the level of B cells (1,2). Since both antigen presenting cells and B cells possess surface Ia molecules, this argument is partially resolved by the recent demonstration in several systems, that Ia molecules are indeed products of Ir genes (3–5). The question remains, however, whether T cells “see” the same Ia epitopes on both antigen presenting cells and on B cells. A direct approach to this question would require knowledge about the nature of the putative “T cell receptors”. In the absence of that information, we attempted to combine the use of the T cell cloning technique and the Ia mutant strain C57BL/6-C-H-2 bm12 (BM12) to examine the Ia specificity by which T cells interact with antigen presenting cells and B cells.