In Vitro Effects of Solubilized HLA-DR--Role in Immunoregulation?

To test the hypothesis that soluble HLA-DR antigens (sHLA-DR), binding to the T-cell receptor (TCR) and/or CD4 structures, compete with and abrogate functions of their cell-bound counterparts, we studied effects of detergent-solubilized, affinity-purified HLA-DR molecules on the DNA synthesis, IL-2, and IL-1 secretion by human peripheral blood mononuclear cells (PBMC). While resting T cells did not show any response, there was a dose-dependent suppression of T-cell responses induced by mitogen (phytohemagglutinin, PHA), recall antigen (purified protein derivative of tuberculin, PPD), or HLA class II alloantigens (Daudi cells). In the PHA system, sHLA-DR affected DR-identical and DR-disparate PBMC with equal efficiency, suggesting a nonspecific interference with accessory functions of cell-bound HLA class II molecules. A competitive ligation of lymphocyte (rather than of monocyte) CD4 is suggested based on the failure of sHLA-DR (i) to potentiate inhibitory effects of anti-CD4 mAb, (ii) to suppress mitogen responses after depletion of CD4+ lymphocytes and also following separate monocyte (vs lymphocyte) pretreatment, and (iii) to induce a reproducible IL-1 secretion inhibition. In the PPD system, suppressive sHLA-DR effects on autologous or DR-identical PBMC significantly exceeded that on DR-disparate PBMC, and in the MLR, third party allogeneic sHLA-DR was exceeded in its suppressive potency both by sHLA-DR pertinent to responder cells and by sHLA-DR pertinent to stimulator cells. These additional specific effects may result from competition (with cell-bound class II restriction and recognition determinants) at the TCR level rather than from peptide competition at the antigen-presenting cell level. Interference by sHLA-DR with the primary and/or accessory signaling may offer new therapeutic strategies in allotransplantation and autoimmunity.