Laurence A. Turka

Antigen specificity of mixed lymphocyte response-induced suppressor cells

The nature of the antigens recognized by mixed lymphocyte response-generated suppressor cells is currently unknown. Previous investigations have yielded conflicting results, with different studies finding that suppressor cells recognize HLA class I antigens, class II antigens, or neither. To characterize the antigens recognized by suppressor cells (modulators) further, we generated 36 different modulators and assayed them for suppressor activity against a random 48-member HLA-typed panel in a total of 473 assays. Logistic regression analysis of the data revealed that suppression was correlated with B and DQ antigenic sharing between the original stimulator (used to generate the suppressor cells) and the test culture stimulator (p = 0.0043 and 0.0277, respectively). A role for DR antigen sharing could not be excluded. Overall, 35% of all suppressed assays could not be accounted for by the sharing of either any classical private HLA antigens, or of HLA-A or B locus cross-reactive group specificities. Suppression in these instances may involve the sharing of minor antigenic determinants, unidentified private HLA epitopes, or possibly another gene related to suppression that exists in linkage disequilibrium with the HLA-B locus or the DQ subregion.

Mixed lymphocyte response-generated suppressor cell specificity in humans is major histocompatibility complex-restricted.

To formally test the hypothesis that allospecificity of the human mixed lymphocyte response-generated suppressor cells is restricted to the major histocompatibility complex, 18 primary mixed lymphocyte responses, using peripheral blood lymphocytes of 10 HLA-typed families, were used to generate suppressor effector cells. Responder lymphocytes shared one HLA haplotype with the stimulator cells. At day 10, the effector cells were tested for their ability to suppress proliferation of 55 test mixed lymphocyte responses consisting of naive autologous lymphocytes as responders and irradiated cells from individual family members as stimulators. Suppression was predicted when the test culture stimulators expressed the same HLA haplotype to which the suppressor cells were primed. There was statistically significant correlation between suppression and HLA haplotype sharing (p = 0.0143). In 6 out of 13 assays, however, we observed suppression that was not predicted on the basis of relevant HLA haplotype sharing. These stimulators shared only HLA-A2 with the priming haplotype. HLA antigen sharing was not seen in the 7 remaining, nonsuppressed cultures. We conclude that, within families, the effector function of in vitro generated suppressor cells is restricted by the major histocompatibility complex.

T Cells Marked by the 2H4 Antigen Function in Allosuppression

A mouse monoclonal antibody (MAb), anti-2H4 (IgG1 subclass), has recently been described (1) that recognizes 200/220 kD glycoproteins (2) of the leukocyte common antigen/T200 family. The 2H4 antigen is found on 42% of unfractionated human T cells, 41% of CD4+ lymphocytes, 54% of CD8+ lymphocytes, and over 30% of both peripheral blood B cells and null cells. In a pokeweed mitogen system that measures B cell immunoglobulin production, the CD4+2H4+ cells were found to be inducers of suppression (1) and CD4+2H4− cells to be inducers of help (3). In the autologous mixed lymphocyte response (AMLR), CD8+2H4+ cells were found to have suppressor effector function (4). Additionally, in a concanavalin A− activated system, suppressor cell activity belonged to the 2H4+ subset of T cells (2). As the role of these subsets have not been established in alloimmunity, we studied the proliferative response and generation of suppressor cells in an allogeneic MLR using 2H4 enriched or depleted cells as the responding population.