Haplotype Preference in Lymphocyte Differentiation

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Abstract
An experimental protocol was designed to study the regulatory activity of carrier-specific F1 hybrid T cells prepared by immunization of unprimed thymocytes within the environment of one or the other of the parental haplotypes. Thus, normal (BALB/c × A/J) F1 (CAF1) thymocytes were transferred into irradiated CAF1 hybrids or parental A/J or BALB/c recipients and primed to KLH. The resulting KLH-specific activated T cells (ATC) were then co-transferred with DNP-specific B cells obtained from CAF1, BALB/c or A/J donors into irradiated CAF1 recipients which were then secondarily challenged with DNP-KLH. The result of this type of experiment revealed that KLH-primed CAF1 ATC primed in a CAF1 recipient provide comparable helper activity for DNP-primed B cells obtained from either parent or from F1 donors. In contrast, CAF1 ATC primed in parental A/J recipients were found to cooperate considerably better with B cells derived from A/J than from BALB/c donors, and vice-versa in the case of CAF1 ATC primed in parental BALB/c recipients. The crucial, and unexpected, observation was that CAF1 ATC prepared in either parental strain failed to provide adequate helper activity for CAF1 B cells. These findings suggested the possibility that during the course of priming of F1 T cells in the environment of one of the parents: 1) helper T cells are generated capable of preferentially cooperating with B cells of the same parental haplotype as used for priming; and 2) suppressor cells are generated capable of preferentially interacting with lymphoid cells bearing the opposite parental haplotype. Indeed, strong evidence was found that suppressor cell activity directed against the opposite parental haplotype does exist in populations of CAF1 ATC prepared in either parental strain, as shown by the capacity of such ATC to inhibit the cooperative response between conventionally primed CAF1 spleen cells and DNP-primed B cells bearing the relevant parental haplotype. Moreover, CAF1 thymocytes exposed in situ to low-dose ionizing irradiation before priming manifested even greater suppressive activity measured in this manner. These observations can be most readily understood by the concept that a population of lymphocytes heterozygous at the major histocompatibility locus consists, either before or after antigen encounter, of separate populations of regulatory lymphocytes, one of which is genetically restricted in its capacity to interact with lymphoid cells bearing one of the parental haplotypes, and a second which is genetically restricted to interact only with lymphoid cells possessing the opposite parental haplotype. The basis of this cellular dichotomy may involve the “restricted expression” of cell interaction (CI) genes and their molecular products in these respective lymphoid subpopulations.

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