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TCRgammadelta-transgenic IL-7(-/-) mice were generated to determine whether T cells containing productively rearranged TCRgammadelta genes have additional requirements for IL-7 within the thymus or peripheral lymphoid tissues. Differences in developmental requirements for IL-7 by TCRgammadelta cells were noted and were linked to derivation from fetal- vs adult-type precursors in the thymus. Although TCRgammadelta cells are absent from IL-7(-/-) mice, TCRgammadelta cells were restored to the thymus and periphery by expression of TCRgammadelta transgenes. Endogenous TCRgamma chains were expressed by IL-7(+/-) but not IL-7(-/-) TCRgammadelta-transgenic mice, providing direct support for findings that IL-7 is necessary for rearrangement and expression of TCRgamma genes. The number of TCRgammadelta thymocytes was 10-fold reduced in TCRgammadelta-transgenic IL-7(-/-) embryos; however, adult TCRgammadelta-transgenic IL-7(-/-) or IL-7(+/-) mice had similar numbers of fetal thymus-derived TCRgammadelta cells in their skin. Thus, fetal TCRgammadelta cells required IL-7 for TCR rearrangement, but not for proliferation or survival in the periphery. In contrast, the numbers of TCRgammadelta cells in other tissues of TCRgammadelta-transgenic IL-7(-/-) mice were not completely restored. Moreover, coincident with the transition from the first to second wave of T cell precursors maturing in neonatal thymus, thymus cellularity of TCRgammadelta-transgenic IL-7(-/-) mice dropped significantly. These data indicated that in addition to TCRVgamma gene rearrangement, TCRgammadelta cells differentiating from late fetal liver or adult bone marrow precursors have additional requirements for IL-7. BrdU incorporation studies indicated that although IL-7 was not required for TCRgammadelta cell proliferation, it was required to prolong the life span of mature TCRgammadelta cells.

The kinetics of various specific and nonspecific immunologic responses were examined in BALB/c mice infected with 17X nonlethal Plasmodium berghei yoelii (a self-limiting infection). The sequence of events after infection was characterized by rapid sensitization of splenic T cells to malaria antigen and polyclonal B cell activation, followed by a period of depressed splenic proliferative responses in vitro to mitogens (PHA and LPS) and malaria (specific) antigen. At the same time, suppressed primary in vitro splenic PFC responses to trinitrophenyl-aminoethylcarbamylmethyl-Ficoll (TNP-F) were seen. This suppression was an active process requiring adherent cells. During this period, levels of antimalarial antibody also increased exponentially. As the infection was cleared, splenic malaria antigen-specific proliferative responses were again observed and splenic PFC and in vitro mitogen responses returned to preinfection levels after variable periods of time. Both splenic proliferative responses to malaria antigen and antimalarial antibody responses remained persistently elevated. In addition, some responses were examined in mice infected with 17X lethal P. b. Yoelii (a fatal infection); in comparison to the early responses of mice infected with the nonlethal substrain, there was a decrease and delay in the development of a splenic T cell response to malaria antigen and a blunted antimalarial antibody response.

After infection with a nonlethal strain of murine malaria (17XNL Plasmodium berghei yoelli), BALB/c mice are then resistant to a lethal strain (17XL P. b. yoelli). BALB/c mice were infected with 17XNL, and challenged 3 weeks later, after clearing their parasitemias, with 17XL. Three weeks thereafter, spleen cells from such immune animals were used to define an early peaking T-dependent (anti-ϑ sensitive) antigen-specific proliferative response when incubated in vitro with 17XL infected RBC, or a saline soluble 17XL antigen preparation. T dependent responsiveness of spleen cells from uninoculated control animals to the 17XL antigen preparation was also observed, but demonstrated a much different (delayed) kinetics from that observed with immune cells.

The cellular basis of immunity to sporozoites was investigated by examining the effect of immunization of T and B cell-deficient C57BL/6N × BALB/c AnN F1 (BLCF1) mice compared to immunocompetent controls. Immunization of T cell-deficient (ATX-BM-ATS) BLCF1 mice with x-irradiated sporozoites did not result in the generation of protective immunity. The same immunization protocols protected all immunocompetent controls. In contrast, B cell-deficient (μ-suppressed) BLCF1 mice were protected by immunization in the majority of cases. The absence of detectable serum circumsporozoite precipitins or sporozoite neutralizing activity in the μ-suppressed mice that resisted a sporozoite challenge suggests a minor role for these humoral factors in protection. These data demonstrate a preeminent role for T cells in the induction of protective immunity in BLCF1 mice against a P. berghei sporozoite infection.

Rosette formation around isolated mouse peritoneal mast cells by sheep erythrocytes coated with DNP37BSA and then reacted with various anti-DNP antibodies was used to investigate the types of antibody capable of binding to these mast cells. Mouse γG2 antibodies, obtained by electrophoretic fractionation, were found to have the ability to bind to mast cells. In addition, the rosette-forming capacity of mouse γG2-coated erythrocytes could be inhibited by the presence of γG1, γG2a, and γG2b purified mouse myeloma proteins, but not by γA of γM myelomas. These results directly demonstrate the existence of a class of antibody molecules which can bind to mast cells but which apparently cannot mediate the anaphylactic release of histamine from those cells. Of the heterologous antibodies studied, rat anti-DNP antibodies were the most effective in forming rosettes around mast cells: rabbit antibodies were much less effective. Guinea pig γG2 antibodies, which also are incapable of mediating anaphylactic reactions in the mouse, were nevertheless capable of binding to mouse mast cells. No receptors for complement could be detected on the surface of mouse peritoneal mast cells.

The graft-vs-host (GVH) activity of thymocytes from BALB/c mice treated 48 to 72 hr previously with 2.5 mg cortisone acetate has been studied with both a spleen weight assay and a mortality assay. Although the cortisone-resistant (CR) thymocytes were 10 times as active as normal thymocytes in the spleen weight assay, they were only 4 to 5 times as active in the mortality assay, and the yield of thymus cells from cortisone-treated donors was only 1/25 that from normal donors: such pretreatment thus resulted in over 50% loss of total GVH reactivity recoverable from the thymus when measured by the spleen weight assay, and approximately 80% loss when measured by the mortality assay. In contrast to normal thymocytes, CR-thymocytes were unable to interact synergistically with normal peripheral lymph node cells; they were also unable to interact synergistically with normal thymocytes. The kinetics of cumulative mortality induced by CR-thymocytes were identical to those of normal thymocytes and strikingly different from those produced by various peripheral lymphoid cell populations. These results suggest that CR-thymocytes represent a unique population of thymus-derived cells and lend support to the concept that different expressions of cell-mediated immune reactions may be initiated by distinct cell types.