Search PubMed⌕ Search

Biomedical subjects

O Stutman

Publications and source records attributed to O Stutman.

At least 37 records · Page 2Linked to original sources
PubMed1986

L3T4+, B2A2+ thymocytes from infant mice produce IL 2 after interaction with accessory cells expressing self class II antigens.

The presence of a thymocyte population in infant (3 to 10 day old), but not adult mice, that produces IL 2 after self class II MHC antigen stimulation is described. The responding thymocyte expresses the antigenic phenotype: Thy-1+, Ly-1+, Ly-2-, L3T4+, B2A2+. Cell-cell mixing experiments and limiting dilution analysis were consistent with a loss of the self-Ia-reactive IL 2-producing thymocyte in the adult, with no evidence for active suppression found. Although thymocytes from adult animals failed to generate IL 2 after self class II stimulation, a similar frequency of IL 2-producing cells was demonstrated in both infant and adult after allo stimulation. These findings, taken with the recent demonstration of IL 2 receptors on neonatal thymocyte subpopulations, demonstrate a mechanism for IL 2 production in the thymus that may play a role in intrathymic differentiation of T cells.

Aging↗
PubMed1986

H-2-linked genes determine the level of the primary in vitro anti-Mls response.

The level of cell proliferation and interleukin-2 (IL-2) production observed in an anti-Mls mixed lymphocyte reaction between spleen cells from H-2 compatible, Mls incompatible mouse strains is determined by the H-2 haplotype of the mouse combination. Thus, while AKR (H-2k) spleen cells stimulated strong Mlsa responses in H-2k responder cells, AKR-H-2b spleen cells stimulated no or negligible Mlsa responses in responder cells from H-2b mouse strains. This effect was observed at the levels of IL-2 production and cell proliferation. The magnitude of the response observed using F1 (H-2k/H-2b) responder cells was found to be a function of stimulator rather than responder cells. The poor stimulatory capacity of AKR-H-2b spleen cells was also shown not to be due to the loss of the stimulatory Mlsa allele during the construction of the congenic strain from AKR and C57BL/6 parental strains. Using stimulator cells from a second series of congenic mice, we found H-2b (strain D1.LP) again to represent a poorly Mlsa stimulatory H-2 haplotype. In addition, H-2q (DBA/1) cells displayed very poor Mlsa stimulatory potential while H-2d (D1.C) cells were efficient Mlsa stimulators. Again the effect was shown to be at the level of the stimulator cells. In toto, our findings indicate that the H-2k and H-2d haplotypes encode strong Mlsa stimulatory potential while the H-2b and H-2q haplotypes determine poor Mlsa stimulatory potential in primary in vitro responses, measured as cell proliferation and IL-2 production.

Alleles↗
PubMed1986

Susceptibility to lysis by natural killer and natural cytotoxic cells is independent of the mitotic stage of the target cell cycle.

Natural cell-mediated cytotoxicity (NCMC) against a number of target cells is mediated by at least two distinct effector populations, with natural killer (NK) and natural cytotoxic (NC) cells being the predominant in the murine system. The studies described in this report examine the role that the phase of the mitotic cycle of the target cell has on its susceptibility to lysis by NC and NK cells. We show that neither the kinetics nor the magnitude of NC cell lysis is altered when assayed using target cells which have been enriched for G1, S, or G2 + M stages of the cell cycle. Similarly, NK cell lysis by fresh or poly-IC augmented effector cells was not effected by target cell cycle.

Animals↗
PubMed1985

The generation of culture activated killer cells (AK) is interleukin-2-dependent and requires self-Ia recognition.

Cytotoxic cells which lack major histocompatibility restriction for lysis are generated when murine spleen cells are cultured in the presence of FCS with or without allogeneic stimulation. The studies reported show that, following 3 days of culture with FCS, murine spleen cell cultures contain at least two cytotoxic populations. The first (AK-YAC), expresses an NK cell phenotype and target specificity while the second (AK-WEHI) shares the characteristics of the NC cell. Generation of the AK-YAC effector cell requires the presence of a pre-AK cytotoxic cell (Qa-5+, Lyt-2-) and is dependent on the generation of interleukin-2 (IL-2) during the culture period, while the AK-WEHI effector is independent of IL-2 production. IL-2 production in the cultures is shown to require syngeneic Ia recognition by an Lyt-1+, L3T4+ T cell. These findings suggest a role for IL-2 in the in vivo regulation of NCMC and describe a mechanism for its production in the absence of antigenic stimulation.

Animals↗
PubMed1985

Specific neonatally induced tolerance to Mls locus determinants.

Neonatal injection of CBA/HT6T6 (H-2k, Mlsb) mice with adult, Mls-incompatible (CBA/J [H-2k, Mlsd] X CBA/HT6T6)F1 spleen cells results in the abrogation of cell proliferation and interleukin 2 (IL 2) production in bulk mixed lymphocyte cultures, when spleen cells from the inoculated mice are tested at 6 to 8 wk of age with stimulator cells expressing the Mlsd of the tolerizing inoculum. In limiting dilution assays, this tolerant state was manifested in a 25- to 550-fold (280-fold average) decrease in the frequency of precursors of Mlsd-responsive IL 2-producing T cells. Tolerance was specific in that the frequencies of precursors of IL 2-producing cells responding to Con A, allogeneic H-2d, and self-Ia were not affected. The observed low frequency of Mls-responsive cells was due neither to extensive chimerism resulting in the dilution of Mlsd-responsive cells by the nonresponsive F1 cells of the inoculum, nor to the action of suppressor cells. These findings indicate that neonatal injection of Mls-incompatible spleen cells produces a state of specific tolerance by a clonal deletion or inactivation mechanism. This specific tolerance supports the view that 1) the Mls locus encodes or regulates the expression of defined alloantigenic determinants and 2) Mls-incompatible responder mice have specific receptors for Mls determinants on clonally distributed IL 2-producing responder T cells.

Animals↗
PubMed1984

Independent inhibition of IL 2 synthesis and cell proliferation by anti-Ia antibodies in mixed lymphocyte responses to Mls.

Whole anti-I region antisera and monoclonal anti-Ia antibodies are capable of totally inhibiting the response of murine spleen cells to the non-H-2 Mls alloantigens. This inhibition was shown to be highly specific for the appropriate Ia and operative at the level of the stimulator cell. Both cell proliferation and interleukin (IL2) production were inhibited; however, the inhibition of cell proliferation was not due only to the inhibition of IL2 production and the inhibition of IL2 production was not solely due to the inhibition of IL1 production. We propose that both the IL2-producing cell and the proliferating cell need to "see" an intact Ia+ cell and perhaps Ia antigens in association with Mls determinants to respond.

Animals↗
PubMed1984

Phenotypic heterogeneity of antisyngeneic tumor killer cells (ASTK) generated in allogeneic mixed lymphocyte reactions.

By using monoclonal antibodies to Thy-1, Lyt-2, and Qa-5 differentiation antigens, we demonstrated a heterogeneity of cytotoxic cells developed in allogeneic mixed lymphocyte responses that lyse tumor cells syngeneic with the responder cells. There are minimally two Thy-1+ populations, one of which is Lyt-2+ and the other Lyt-2-. There is probably also a Thy-1- population. Most of the Lyt-2- tumor killer cells are Qa-5+, and most of the Lyt-2+ tumor killer cells are Qa-5-.

Animals↗
PubMed1984

Early loss of precursors of CTL and IL 2-producing cells in the development of neonatal tolerance to alloantigens.

Bulk culture and limiting dilution analysis (LDA) were used to follow the ontogeny of the tolerant state in CBA/ HT6T6 mice neonatally tolerized to allogeneic histocompatibility antigens. Advantage was taken of the fact that the lymph nodes (LN) of young mice show immunocompetence before spleen cells do, allowing analysis of actual reactivity as early as 1 wk of age. At 1 wk, the LN cells of mice tolerized i.v. showed a loss of CTL reactivity in bulk culture specific for the tolerizing antigens; a corresponding specific decrease was seen in the frequency of CTL precursors (CTLp). At the same age, however, proliferative responses and interleukin 2 (IL 2) production in MLC were nonspecifically depressed in the tolerized animals. LDA of IL 2 producer precursor frequency (IL- 2Tp ) showed that there was a nonspecific loss of 50% of functional alloreactive IL- 2Tp , accompanied by a larger specific decrease of 90% in the frequency of IL- 2Tp responding to the injected alloantigens. These characteristics of the tolerant state persisted through at least 4 wk of age. Neither the proliferative nor CTL response deficiencies could be overcome by the addition of Con A supernatant containing IL 2. Mixing experiments failed to show evidence of suppressor cell involvement in the loss of the proliferative response. Our results indicate that the specific loss of alloreactivity after tolerization is due to clonal inactivation or deletion of both CTLp and IL- 2Tp , which is obvious as early as 7 days of age. In addition, the differences in the specificity of the clonal inactivation between CTLp and IL- 2Tp suggest the existence of independent mechanisms for tolerization.

Animals↗
PubMed1984

T cell repopulation from functionally restricted splenic progenitors: 10,000-fold expansion documented by using limiting dilution analyses.

Mice depleted of T cells by thymectomy, lethal irradiation, and reconstitution with Thy-1-depleted syngeneic bone marrow were given graded doses of splenic T cells to see whether post-thymic cells had the ability to regenerate immune function in these hosts. Using limiting dilution methods to estimate the number of antigen- and mitogen-responsive cells in recipients 12 to 20 wk after reconstitution, we found that new helper and cytotoxic precursor cells were produced, but attained levels only 10 to 20% of normal. Because these repopulated mice were able to produce nearly normal levels of helper and cytotoxic activity in conventional, high density cultures, despite their relative paucity of precursors, we infer that their normal function in conventional assays may reflect a balanced deficiency of effector and regulatory cell types. Surface phenotyping of the progenitor cells responsible for repopulation showed that Lyt-2- cells were required for helper cell regeneration and that Lyt-2+ cells acted as progenitors only for the cytotoxic lineage, contrary to earlier speculation that the splenic Lyt-1+ 2+ (Ly-123) pool included cells antecedent to both effector lineages. Comparison of the number of injected progenitors needed to produce repopulation with the number of new precursor cells eventually produced suggests that the relevant progenitors are able to undergo 10,000-fold expansion in 12 to 20 wk. Numerical expansion in the periphery from thymic-processed cells could well be a major source of new lymphocytes in adult mice.

Animals↗
PubMed1983

Murine non-lymphoid tumors are lysed by a combination of NK and NC cells.

Natural cell-mediated cytotoxicity (NCMC) against a variety of tumor targets is mediated by a heterogeneous group of effector cells with the natural killer (NK) and natural cytotoxic (NC) cells being the predominant prototypes in mice. This report shows that non-lymphoid tumor targets, mostly derived from chemically induced fibrosarcomas, are susceptible to either (1) NK-mediated lysis with all the activity being the function of a poly-IC augmentable Qa-5+ effector cell; (2) NC-mediated lysis with all activity being the function of a Qa-5- cell not augmented by poly-IC; and (3) a combination of NK-and NC-mediated lysis with activity being the function of both Qa-5+ and Qa-5- cells, the NK (Qa-5+) augmented by poly-IC. These studies further support the view that murine NC and NK cells are distinct and collectively make up the NCMC system, and also that the previous association of NK cells with lymphoid tumor lysis and NC cells with non-lymphoid tumor lysis is not a valid one.

Animals↗
PubMed1983

The activity of natural cytotoxic cells is augmented by interleukin 2 and interleukin 3.

Murine natural killer (NK) and natural cytotoxic (NC) cells showed different patterns of augmentation of lytic activity after preincubation for 24 h with either poly-IC, interleukin 2 (IL-2), or interleukin 3 (IL-3): (a) Poly-IC augmented only NK cells, with no effect on NC activity, as we have previously observed (4); (b) IL-2 augmented both NK and NC activity; and (c) IL-3 augmented only NC lysis, without affecting NK activity. In addition, both precursor and the augmented effector cells showed differences in expression of the Qa-5 surface marker: NK precursors and effectors are Qa 5+, whereas NC precursors and effector cells are Qa-5-.

Animals↗
PubMed1983

Analysis by limiting dilution of interleukin 2-producing T cells in murine ontogeny.

The ontogeny of interleukin 2 (IL 2) production in young CBA/HT6T6J mice was studied using both bulk culture and limiting dilution methods. The ability of spleen cells in bulk culture to produce IL 2 in response to concanavalin A (Con A) was found to rise through the first 2 weeks of life, from no production at day 1, through 20 units/ml at day 6, to 80-100 units/ml in adults. No evidence for suppression of IL 2 production by young spleen was found. Limiting dilution analysis of both young spleen and young lymph node (LN) shows that young spleen has a much lower complement of cells producing IL 2 in response to Con A or allogeneic stimulation than does adult spleen. The frequency of 6-day spleen cells producing IL 2 in response to Con A is 1/1000, while the adult frequency is approximately 1/50. Young LN, in contrast, has levels of IL 2-producing cells close to those of adult LN, with a frequency of responders to Con A of 1/20. No evidence was found for a deficiency in IL 2 production on a per cell basis, in either 6-day spleen or LN. In examining allogeneic reactivity, a high frequency of cells reacting to strong Mls stimulation was found in both young and adult spleen and LN.

Aging↗