Carbohydrate moieties of major histocompatibility complex class I alloantigens are not required for their recognition by T lymphocytes.

Abstract

Cytotoxic T lymphocytes (CTL) have been implicated as effectors in allograft rejection and in control of viral infection. Induction of a cytolytic response requires T cell recognition of foreign major histocompatibility complex (MHC) class I glycoproteins, or syngeneic MHC antigens along with a foreign (i.e., viral) protein. This recognition process leads to proliferation and differentiation of precursor cells to effector CTL capable of lysing target cells that bear the same antigens. While class I oligosaccharide residues do not contribute to serologic determinants (1-4) their role in T cell recognition has remained unclear. Modification of the carbohydrates of membrane glycoproteins on intact stimulating or target cells has been observed to inhibit (1, 5, 6), stimulate (7, 8), or have no effect (2, 6, 9) on T cell responses. In all of these cases, it is difficult to conclude whether the observed effects were due to altered MHC antigen oligosaccharides, since modifications could not be limited to the surface glycoprotein of interest, and the extent of modification could not be readily determined.Class I antigens of the murine MHC (H-2) are polymorphic two-chain cell surface glycoproteins consisting of a glycosylated transmembrane heavy chain (Mr 40,000-50,000) noncovalently associated with /32-microglobulin, an invariant, nonglycosylated polypeptide (Mr 1 1,500). Amino acid and DNA sequence data suggest that the extracellular portion of the heavy chain can be divided into three globular domains of ~91 amino acids each (~, c~z, and as). Determinants recognized by T cells appear to reside in the c~l and a2 domains (10), regions of maximal amino acid variability (11). Glycosyl moieties are also present in these regions, N-linked to asparagine residues at positions 86 and 176. A third glycan attachment site in K d, D b, and L d antigens is at residue 256 (11).Purified class I alloantigen in artificial membranes (liposomes) can stimulate a CTL response of comparable magnitude to that obtained using intact stimulating cells when added to in vitro cultures of spleen cells from mice previously primed to the same alloantigen (12). The magnitude of the response to the liposomes provides a direct measure of the effectiveness of antigen recognition

T cell recognition of a tumor-associated glycoprotein and its synthetic carbohydrate epitopes: stimulation of anticancer T cell immunity in vivo

“…Monoclonal antibodies to various cellular antigens [33,42] or synthetic carbohydrate antigens [31,34] may have their fine specificities determined by immunodominant carbohydrate determinants. Attempts to resolve the controversy concerning recognition of carbohydrate determinants by T cells showed that alteration of the carbohydrate portion of an antigen (1) inhibited [5,30], (2) stimulated [7,29], or (3) had no effect [21,35] on the ability of T cells to recognize and respond to the antigen. These controversial results may have been due to the fact that most T cell responses appear to be directed against processed antigen in association with self-restricting antigens of the MHC [45].…”

Cytotoxic T lymphocytes from HLA-A2 transgenic mice specific for HLA-A2 expressed on human cells.

“…It is unlikely that these epitopes result from differences in post-translational modification of the HLA-A2.1 molecule in human and murine cells, since no such differences have been detected (6,7). In addition, the carbohydrate side chain has been shown not to influence CTL recognition of class I molecules (15)(16)(17). The recognition of human HLA-A2.1-expressing cells from different individuals and tissues also suggests that these epitopes do not arise from the association of the HLA-A2.1 molecule with human minor histocompatibility or tissue-specific antigens .…”

Influence of Glycosylation Inhibition on the Binding of KIR3DL1 to HLA-B*57:01

“…Reports of the importance of N -glycosylation for KIR:HLA binding are scarce, save for one study suggesting that the HLA class I N -glycan does not influence KIR binding [ 26 ]. In contrast, several studies reported the consequences of HLA class I N -glycosylation modifications on T-cell receptor (TCR) binding [ 23 , 27 – 29 ]. Those reports all concluded that TCR binding to HLA class I (and MHC class I in mice) is independent of HLA class I glycosylation, given the relatively long distance between the TCR binding site and the HLA class I N86 glycan.…”