Approximately 5 yr ago the first observations that documented genetic restrictions imposed by genes within the major histocompatibility complex (MHC) 1 upon cooperative interactions between T lymphocytes and macrophages and between T lymphocytes and B lymphocytes were described (1-3). Later, it was found that the most efficient lysis of target cells by specific cytotoxic T lymphocytes (CTL) occurred when the CTL and target cell, respectively, shared gene identities in the mouse H-2 complex (4-8). Genetic mapping studies documented that gene(s) controlling T-B-cell interactions are located in the/-region of the mouse 1-1-2 complex (9), whereas those involved in CTL-target interactions are located in the K and D regions of/_/. 2 (10, 11).The subject of MHC-linked genetic restrictions on cell-cell communication processes has evoked controversy both in terms of the extent of such constraints on cell-cell interactions and on the best possible interpretations of such restrictions (12-14). Essentially two major concepts have evolved to explain these genetic restrictions on cell interactions. The first hypothesis, which stemmed from analysis of such restrictions in T-B-cell interactions, considered that interactions among various cell types in the immune system are mediated by cell interaction (CI) molecules located on the cell surface, at least some of which are encoded by MHC genes (i.e./-region genes in this case), and which are quite distinct from the lymphocyte receptors specific for conventional antigens (13-15). The CI molecule concept therefore emphasizes a dual recognition mechanism which involves at least two distinct molecular interactions in lymphocyte activation, one utilizing antigen-specific receptors and the second consisting of reactions between the relevant CI structures and their corresponding receptors. The second major concept, derived primarily from studies in the CTL systems, considered that T lymphocytes have receptors which recognize not antigen alone, but antigen in some form of association with MHC gene products on cell surface membranes; this concept of "ahered-setf" (16) recognition by T lymphocytes differs substantially from the CI molecule concept in predicting the existence of a single receptor on T cells simultaneously recognizing modified determinants on the cell surface. To date, no definitive proof has been obtained to establish which of these two models is correct.

No abstract

This study was conducted to analyze the extent to which the major histocompatibility complex (MHC) a genotype of the thymus restricts the cooperating phenotype of helper T cells with respect to their ultimate ability to interact effectively with partner B lymphocytes in the development of antibody responses. These studies, like others reported previously (I, 2), made use of artificially constructed bone marrow chimeras prepared by reconstituting aduh-thymectomized, lethally irradiated F1 mice with syngeneic F1 bone marrow, together with transplanted thymuses from either F1 or parental donors. Reconstituted mice of these types were then immunized with keyhole limpet hemocyanin (KLH) and their KLH-specific helper T cells so induced were tested for the cooperative helper activity they could provide to 2,4-dinitrophenyl (DNP)-primed B lymphocytes derived from conventional F1 or parental donors in developing secondary anti-DNP antibody responses to DNP-KLH. The results clearly show that the thymus influences little, and certainly does not restrict, the partner cell preference displayed by helper T cells differentiating in such environments. Moreover, the extent of thymic influence differed depending on the class of antibody being produced with the help of such cells.This investigation is an extension of earlier studies in this (3) and other laboratories (4-10) which have addressed the predictions of the concept of adaptive differentiation (3,(11)(12)(13)(14). This notion ascribes the partner cell preferences of various cells of the lymphoid system, known to be genetically controlled by various regions of the MHC (15), to processes of selection that occur early during cell differentiation and which are determined by the MHC phenotype of the environment in which such differentiation occurs (3,(11)(12)(13)(14). The first experiments supporting this concept were performed * Publication 94 from the Department of Cellular and Developmental Immunology and publication

Several years ago, we reported that T cells from (responder × nopresponder) F1 hybrids primed to the synthetic terpolymer, L-glutamic acid, L-lysine, L-tyrosine (GLT), 1 to which responses are governed by H-2-1inked Immune response-GLT genes, were restricted in their ability to provide GLT-specific help for 2,4-dinitrophenyl (DNP)-primed B cells from the respective parental mice in response to DNP-GLT (1). Thus, such F1 T cells were able to provide normal helper activity for DNP-specific B cells from responder, but not from nonresponder, donor mice. This finding contrasted sharply with the indiscriminant ability of F1 T cells to interact effectively with partner B cells from either parent when the carrier antigen employed was not one to which responses were governed by a known Ir gene. This observation has subsequently been confirmed by others in studies conducted in mice (2, 3) and guinea pigs (4).These observations were interpreted as an indication that in heterozygous individuals independent subpopulations of interacting T lymphocytes existed, one each corresponding to the respective parental type (1,5,6). Hence, we envisaged that stimulation of a (responder × nonresponder) F1 T-cell population by GLT would sensitize only the population of T cells able to recognize and react with the functional cell-interaction (CI) phenotype of the responder parent; F1 T cells corresponding to the nonresponder parent CI phenotype would not be stimulated by GLT. This situation would therefore be manifested as the defective ability of F1 T cells to interact with nonresponder B cells, irrespective of the antigen specificity of the latter. This original interpretation (1, 5, 6) has been reinforced by the subsequent demonstrations of the existence of independent Wl T-cell subpopulations that are reactive with each respective parental CI phenotype (7-12).

The experiments presented herein demonstrate that F1-parent T-B cell cooperation in vivo is significantly diminished by the addition of lymphoid cells of opposite parental type. This inhibition phenomenon is not a straightforward allosuppression mechanism as (a) it can be induced by parental lymphoid cells depleted by T cells, (b) it does not operate on cooperative interactions between homologous T and B cells of opposite parental type, and (c) absolutely requires the presence of F1 cells as participants in the reactions generated. The possible involvement of alloantibodies produced aberrantly under the experimental conditions employed has been ruled out by direct macrophage/antigen-presenting cell components of the reactions has been excluded. Because the presence of parental lymphoid cells only affects cooperative interactions between F1 T cells and B lymphocytes of opposite parental type but has no inhibitory effect on cooperative interactions between homologous F1, T and B cells, this (and other points discussed herein) strongly argues for the existence of one or more subsets of F1 interacting partner cells that are uniquely specific for F1, as distinct from either parental type cell interaction determinants. For reasons discussed, it appears that the most likely mechanism underlying such parental cell-induced inhibitory effects on F1-parent partner cell interactions is the development of anti-self cell interaction structure responses by F1 cells against the relevant self-specific cell-interaction structures of the parental partner cells involved.