The results of this study provide compelling evidence for the existence of the gene or genes controlling optimal T-B-cell cooperative interactions in the designated I region of the H-2 gene complex. Previously, we have speculated that the relevant gene(s) involved may well be located in this region based on several observations from our earlier work in this area (3, 5, 6). Thus, in the preceding paper, we showed that T and B cells from B10.BR and A strain mice developed effective cooperative interactions in vitro to DNP-KLH in a system identical to the one reported herein. Since these mice differ for genes in the S and D regions of H-2 but are identical for K and I region genes, we were able to localize the critical genes to the K-end of H-2.

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.

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Delayed-type hypersensitivity (DTH) responses specific for the phosphorylcholine (PC) hapten were induced in BALB/c mice by immunization with syngeneic peritoneal exudate cells (PEC) coupled with diazotized phenyl-phosphoryl-choline. PC-specific DTH responses were elicited in such immunized mice after footpad challenge with PC-derivatized syngeneic spleen cells. Moreover, PC-immune lymph node cells could passively transfer PC-specific DTH responses to naive BALB/c mice and it was possible to demonstrate that the cells responsible for such passively transferred responses were T lymphocytes. Because the T-15 idiotypic determinant displayed on the TEPC-15 PC-binding myeloma protein is known to be a dominant idiotype associated with anti-PC antibody responses in BALB/c mice, an analysis was made of the effects of anti-T-15 idiotypic antibodies on the induction and expression of murine PC-specific DTH responses. Repeated injections of anti-T-15 idiotypic antiserum, raised in A/J mice by immunization with TEPC-15 myeloma protein, into recipient BALB/c mice both immediately before and after sensitization with PC-PEC virtually abolished the development of PC-specific DTH responses. Although administration of anti-T-15 antiserum effectively inhibited the induction phase of PC-specific DTH responses, these anti-idiotypic antibodies had no suppressive activity at the effector phase of these responses. The inhibition observed with anti-T-15 antibodies was highly specific for the PC hapten, and for PC-specific DTH responses of BALB/c but not A/J mice. Studies were conducted to address the possibility that anti-Id treatment induced suppressor T lymphocytes capable of specifically inhibiting the activity of PC-specific T cells participating in DTH responses. The results demonstrate that idiotype-specific suppressor T cells are, indeed, induced by treatment with anti-Id; moreover, such suppressor T cells, once induced, are highly effective in abrogating both the induction and the effector phases of PC-specific T cell-mediated DTH responses in BALB/c mice.

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