This proposal is designed to seek basic information on the properties of unprimed L3T4+ and Lyt-2+ T cell subsets responding to H-2 alloantigens. Particular emphasis is placed on studying Lyt-2+ cells since less is known about these cells than L3T4+ cells. Three broad areas of investigation are proposed: 1) Variation in the responsiveness of Lyt-2+ cells. Although purified Lyt-2+ cells can give very high responses to class I (but not class II) H-2 alloantigens in the absence of added lymphokines, certain class I differences are much less immunogenic than others. Moreover, the general level of responsiveness of Lyt-2+ cells can vary considerably from one strain to another. Various approaches, including the use of thymus-grafted chimeras and recombinant inbred mice, will be used to seek further information on these two levels of variability in the responsiveness of Lyt-2+ cells. 2) Stimulatory requirements for Lyt-2+ cells in vitro. Whereas L3T4+ cells respond solely to Ia+ cells, Lyt-2+ cells can be stimulated by class I differences expressed or certain Ia- cells. Whereas normal allogeneic T cells are nonstimulatory for Lyt-2+ cells unless supplemented with lymphokines, Lyt-2+ cells respond strongly to a subpopulation of Thy 1- Ia- cells present in spleen and marrow. Unprimed Lyt-2+ cells also respond to certain Ia- tumor cells, including T tumors. By scrutinizing the response of Lyt-2+ cells to these tumor cells, we hope to obtain information on what signals are needed for Lyt-2+ cell induction. 3) In vivo functions of T cell subsets. Four approaches will be used to seek further information on the behavior of T cell subsets in vivo. First, the Winn assay will be used to examine the capacity of Lyt-2+ cells to reject various types of allogeneic tumor cells; preliminary work has shown that mixing allogeneic tumor cells with unprimed Lyt-2+ cells and injecting the cells subcutaneously into irradiated mice prevents the appearance of macroscopic tumors. Second, studies with bone marrow chimeras will be used to determine whether Lyt-2+ cells have the capacity to recognize allo class I molecules on non-marrow derived cells. Third, detailed information will be sought on the capacity of L3T4+ and Lyt-2+ cells to cause lethal graft-versus-host disease directed to allo class I vs. class II differences. Fourth, further information will be sought on the capacity of Lyt-2+ cells to mediate rejection of skin allografts.
| Boyman, Onur; Ramsey, Chris; Kim, David M et al. (2008) IL-7/anti-IL-7 mAb complexes restore T cell development and induce homeostatic T Cell expansion without lymphopenia. J Immunol 180:7265-75 |
| Boyman, Onur; Cho, Jae-Ho; Tan, Joyce T et al. (2006) A major histocompatibility complex class I-dependent subset of memory phenotype CD8+ cells. J Exp Med 203:1817-25 |
| Surh, Charles D; Boyman, Onur; Purton, Jared F et al. (2006) Homeostasis of memory T cells. Immunol Rev 211:154-63 |
| Kovar, Marek; Boyman, Onur; Shen, Xuefei et al. (2006) Direct stimulation of T cells by membrane vesicles from antigen-presenting cells. Proc Natl Acad Sci U S A 103:11671-6 |
| Rubinstein, Mark P; Kovar, Marek; Purton, Jared F et al. (2006) Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci U S A 103:9166-71 |
| Ishimaru, Naozumi; Kishimoto, Hidehiro; Hayashi, Yoshio et al. (2006) Regulation of naive T cell function by the NF-kappaB2 pathway. Nat Immunol 7:763-72 |
| Surh, Charles D; Sprent, Jonathan (2005) Regulation of mature T cell homeostasis. Semin Immunol 17:183-91 |
| Sprent, Jonathan (2005) Direct stimulation of naive T cells by antigen-presenting cell vesicles. Blood Cells Mol Dis 35:17-20 |
| Lenz, Derek C; Kurz, Sabine K; Lemmens, Edward et al. (2004) IL-7 regulates basal homeostatic proliferation of antiviral CD4+T cell memory. Proc Natl Acad Sci U S A 101:9357-62 |
| Hwang, Inkyu; Shen, Xuefei; Sprent, Jonathan (2003) Direct stimulation of naive T cells by membrane vesicles from antigen-presenting cells: distinct roles for CD54 and B7 molecules. Proc Natl Acad Sci U S A 100:6670-5 |
Showing the most recent 10 out of 142 publications
