Specific Positive Selection of Lymphocytes Reactive to Strong Histocompatibility Antigens

Abstract

The population of thymus-derlved (T) lymphocytes reactive to strong histocompatibility (H) 1 alloantigens (HARC) is peculiar in two respects in comparison to lymphocytes~responsive to other antigens: first, the T cells reactive to any given strong H antigen outnumber by two to three orders of magnitude the T cells responsive to more conventional antigens (1-3); and secondly, the frequency of HARC to a given H alloanfigen is not increased as a consequence of immunization in vivo (4-6). Just how fundamental these distinctions are between immune reactivity to H alloantigens and other antigen systems is not presently known. For example, the high frequency of HARC raises the possibility that these cells are multipotential, having the capacity to react to several different antigenic determinants. It is clear now that totipotentiality with respect to immune reactivity to H alloantigens can be excluded for HARC, since lymphocyte populations can be experimentally depleted of cells reactive to one H alloantigen, while retaining undiminished reactivity to other antigens (7-8). These "negative" selection experiments do not, however, allow conclusions concerning the ability of cells reactive to one H alloantigen to react to other H alloantigens or to conventional antigens. To examine this question it is essential to prepare pure populations of HARC with reactivity to a single H alloantigen so that the ability of these cells to react to other H alloantigens and to conventional antigens can be tested. This communication describes a procedure which appears to provide specific "positive" selection of cells reactive to chosen strong H alloantigens, and it also illustrates preliminary results obtained using this procedure.Previous studies have shown that parental strain T lymphocytes are induced to proliferate in the mixed lymphocyte interaction (MLI) when they are mixed with alloantigen-bearing cells derived from F1 animals (9), but disappear rapidly under the same culture conditions in the absence of antigen (2). This antigen-dependent survival of cells in the MLI could represent the progeny of lymphocytes specifically reactive to the priming antigens in the culture systems, and if so, these selected progeny should inherit the specific reactivity of their parents.

Specific transplantation tolerance induced by autoimmunization against the individual's own, naturally occurring idiotypic, antigen-binding receptors.

“…It is well known that a high percentage of T lymphocytes in a normal individual is precommitted to react across the major histocompatibility barrier of the species as measured by activation of function in mixed leukocyte cultures or graft-versus-host reactions (4)(5)(6). Recently, we have been able to confirm the unusual high figures in normal lymphocytes using specific anti-idiotypic antibodies (7).…”

Thymus Derived Killer Cells: Specificity of Function, and Antigen Recognition

“…Thus these experiments clearly show that the requirements for inducing T killer cell proliferation and for killing are different. Howard & Wilson (1974) recently reported that rat lymphocytes, reactive to strong histocompatibility antigens in vitro, if propagated in thymus-depleted animals for prolonged periods of time, not only show a strong proliferative response to the original priming alloantigens but also to others. It should be stressed, however, that this behavior of T killer cells in a secondary response appears to be different from the primary response, in that T killer cell sensitization in the primary response usually gives rise to effector cells specific for the sensitizing cells only.…”

Genetic and cellular aspects of xenogeneic mixed leukocyte culture reaction.

“…The recently described "primed lymphocyte typing" (PLT) assay (2) has made it possible to determine indirectly the genetic control of xenogeneic MLC. Sensitization in a mixed lymphocyte culture positively selects for memory cells which give a rapid secondary response upon restimulation with cells from the initial stimulator (3,4). Studies in human families (2,(5)(6)(7) showed that restimulation is caused by the same LD determinants of the major histocompatibility complex (MHC) that induce primary MLC responses.…”