Constitutive functional heterogeneity without detectable somatic mutation of antigen receptor genes in helper T cell clones: possible regulation by novel HLA class II "DY" determinants.
The majority of interleukin 2-dependent HLA class II alloreactive human CD4-positive helper T-cell clones (TCC) presented the phenomenon of constitutive intraclonal heterogeneity, as reflected by limiting dilution analysis of changing frequencies of autonomously proliferative cells within the monoclonal population. Moreover, at 30-35 population doublings, these TCC lost their allospecific proliferative and helper capacity (phase I) and instead acquired strong antigen-non-specific suppressive activity (phase II). The TCR was still expressed at the same level on the cell surface. As shown by stable and identical rearrangement profiles of their T-cell receptor beta- and gamma-chain genes in both phases I and II, this constitutive change of function was probably not due to somatic mutation of the genes coding for the antigen-specific receptor. Moreover, antigen specific reactivity was retained in phase II TCC by the criterion of specifically stimulated secretion of granulocyte/macrophage colony stimulating factor. The preprogrammed intra-clonal functional flexibility is explained here by invoking a novel regulatory mechanism mediated by a fourth group of HLA class II determinants. When TCC were used as stimulators with the appropriate primed responders, it could be demonstrated that phase I autonomously proliferative non-suppressive T-helper lines failed to express certain novel lymphocyte activating determinants (LADs), whereas after their acquisition of suppressive function (phase II) these LADs were present. These stimulatory moieties appeared to represent a novel class II-like structure as established by serology, immunochemistry and functional characterization employing monoclonal antibodies to block stimulation. These operationally designated "DY" determinants are primarily and thus far exclusively involved in the induction of antigen non-specific suppressor cells. It is proposed that the intra-clonal changes of T-cell function described here are mediated by a switch in the utilization of qualitatively distinct class II-like restriction elements. The functional status of the phase I TCC can be altered by a switching over to the engagement of "DY" determinants in phase II. Thus, an autostimulatory and self-maintaining suppressive network may operate in extended inductive phases of human HLA restricted T-cell responses.
D002462:Cell Membrane / Q000276:immunology; D002999:Clone Cells / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006681:HLA-D Antigens / Q000276:immunology*; D006801:Humans; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis; D009154:Mutation; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D000939:Epitopes; D006681:HLA-D Antigens; D008222:Lymphokines; D011948:Receptors, Antigen, T-Cell