Sensitized thymus-derived (I) lymphocytes can transfer delayed-type hypersensitivity (DTH) to naive mice only if there is identity at the major histocompatibility complex (MHC). The MHC region responsible differs according to the antigen used for sensitization. For transfer of DTH to fowl gamma globulin identity at I-A is necessary; for dinitrofluorobenzene, however, identity at either K, D, or I region is sufficient. T cells of one genotype, sensitized in a chimeric environment, transferred DTH to both parental strains even though these were MIC incompatible. However sensitized F1 mice to naive mice of the parental strain that are competent to reject the F1 cells.The requirement for compatibility at some genes of the MHC for DTH transfer may be taken to indicate that effective interaction between sensitized lymphocytes and cells presenting antigen (probably macrophages) are governed by cell surface structures coded by MHC genes. The genetic constraints imposed on this interaction may be explained in one of two ways.(1) It is possible that the antigen binding receptor on the T cell has a combining site directed towards a structure on the macrophage that represents an antigen-associated modification of the I region determinant or, alternatively, an I region modification of the processed antigen. This, represented diagrammatically in model I of Fig. 1, is based on the model favored by Doherty, Blanden, and Zinkernagel (4) to explain the genetic constraints imposed by the K and D regions of the MHC for cytotoxic T lymphocytes. (2) An alternative possibility envisages the T cell receptor as a compound, with one part being the combining site directed towards the antigen and the other part consisting of a cell interaction molecule coded by the I region which is not a receptor for antigen. The T cell would become effective only if two reactions occurred at its surface: one would be the binding of the antigen to the combining site, and the other would be some conformational change induced in the cell interaction molecule after matching another identical molecule on the surface of the macrophage. This model (shown as model II in Fig. 1

The Ly and Ia phenotypes of T lymphocytes involved in different functions were characterized by the use of specific antisera. T cells responsible for delayed-type hypersensitivity (DTH) and for helper functions were found to be Ly-1+,2- in contrast to cytotoxic T cells and T cells responsible for suppression of antibody responses which were Ly-1-,2+. Unlike some primed helper cells, T cells involved in DTH were Ia-. Suppressor cells in the system were Ia+.

Sensitized lymphocytes can transfer a state of delayed-type hypersensitivity to soluble protein antigens to naive mice only if donor and recipient share the I-A region of the H-2 gene complex. Identity at the K or D region is not essential. The restriction is unlikely to result from ineffective homing of the injected cells or from their early destruction. It is thought to reflect a requirement for an Ir-gene controlled mechanism which governs effective interaction between sensitized T lymphocytes and antigen presented on the surface of macrophages.There is considerable evidence that T (thymus-derived) cell activities are regulated by genes in the major histocompatibility complex (MHC). Thus, in mice, histoincompatible T cells may not function as helpers for antibody-forming precursor B (bone-marrow-derived) cells in some transfer systems (1). In guinea pigs, maximal lymphocyte proliferation in response to antigen-pulsed macrophages occurs in vitro only when lymphocytes and macrophages have at least part of the MHC in common (2). Lysis of virus-infected or chemically modified target cells by cytotoxic T cells in mice is possible only when these cells share one H-2 haplotype (3, 4). Requirement for H-2 compatibility is also evident in vivo in immunopathology induced by T cells (5) and in T-cellmediated protection against bacterial infections (6). In the case of specific lysis of target cells, identity is essential at the K or D regions of the H-2 complex, not at the I region (4, 7). On the other hand, in order for cooperative interactions to occur between T and B lymphocytes in some antibody responses, identity is required at the I region, not at the K, D, or S regions (8). Likewise, optimal induction of helper T cells by macrophage-associated antigen was found to require identity at the I region of the MHC (9).Delayed-type hypersensitivity (DTH) may be considered as a model for T-cell-mediated inflammatory responses (10). The present investigations were designed to determine whether successful transfer of DTH by lymphoid cells from sensitized to naive mice might be restricted by genes of the MHC. These studies were made possible by the use of congenic strains of mice and of a new radioisotopic assay which gives an objective measure of the extent of DTH in mice (11,12).MATERIALS AND METHODS Mice. Female mice (2-3 month old) were used for sensitization. Mice of both sexes served as recipients of sensitized cells. Highly inbred specific pathogen-free CBA/CaHWehi, C57BL/6JWehi, and BALB/cAnBrWehi mice were transferred to conventional rooms for the duration of the experi- Sensitization. Two days before sensitization mice were given 200 mg/kg of cyclophosphamide (Endoxan-Asta) subcutaneously since this was found to allow maximal levels of sensitivity in mice (11). For sensitization to fowl (chicken) gamma globulin (FGG), the antigen was emulsified in complete Freund's adjuvant and 0.15 ml (containing 400 sg of FGG) was injected in three subcutaneous sites divided between the two hind footpads and abdomen. For s...

Delayed type hypersensitivity (DTH) lesions have been difficult to evaluate objectively in the mouse because they are usually assessed in terms of an increase in footpad swelling or ear thickness. We have developed a radioisotopic method which not only reduces the observer’s error but also gives an objective measurement of the cellular activity in the lesions. In brief, 10 μl of the test antigen is injected intradermally into the left pinna and either nothing or the same volume of a control solution into the right. 10 h later, a 2-μCi pulse of 5-iodo-2′deoxyuridine-¹²⁵I is given intravenously, the ears cut off at the hairline 16 h later and the radioactivity counted in a gamma spectrometer. The following was obtained as evidence that the increased radioactivity of the left pinna over the right was a measure of the extent of a DTH response: (1) the ear reaction was delayed in mice without serum antibodies becoming maximum at 24 h; (2) there was a mononuclear cell infiltration in the left pinna and autoradiographs revealed radioactive label bound to these cells; (3) athymic mice could not develop a 24-hour ear reaction, and (4) antigens known not to activate T cells did not elicit the ear response. Cell transfer studies will be described in a subsequent paper. Different sensitization regimes were required with different antigens in order to obtain the highest levels of DTH as tested by the ear response, and the maximal ear reaction occurred at different days. The ear reaction showed the specificity expected of a DTH response.

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