Broad programming by IL-2 receptor signaling for extended growth to multiple cytokines and functional maturation of antigen-activated T cells.

Coincident production of IL-2 and induction of high-affinity IL-2R upon TCR engagement has precluded a clear distinction for the biological outcome of signaling through TCR/costimulatory molecules vs the IL-2R. Using a novel transgenic mouse on the IL-2Rbeta(-/-) genetic background, this study has separated the relative outcome of signaling through the TCR and IL-2R. We show that stimulation through the TCR and CD28 or CD40 ligand directly leads to T cell activation and several rounds of proliferation in an IL-2-independent fashion.

Normal lymphoid homeostasis and lack of lethal autoimmunity in mice containing mature T cells with severely impaired IL-2 receptors.

The importance of IL-2Rbeta function for immune regulation is highlighted by the severe impairment in lymphoid cell function in IL-2Rbeta-deficient mice. It has been speculated that failed IL-2/IL-2R signaling in peripheral T cells causes the associated autoimmunity, imbalanced peripheral lymphoid homeostasis, and defective T cell function. This study explored the requirement for IL-2Rbeta function in mature T lymphocytes.

Regulation of T lymphocyte function by glycosylphosphatidylinositol (GPI)-anchored proteins.

Monoclonal antibody binding to GPI-anchored proteins, e.g. Thy-1 and Ly-6, on the surface of T lymphocytes usually leads to stimulation of interleukin-2 production.

Subsets of activated CD4 T lymphocytes refractory for secretion of IL-2 are distinguished by expression of Ly-6A/E in BALB/c mice.

Ly-6A/E, a cell surface glycosylphosphatidylinositol-anchored protein that modulates T cell activation, is expressed on developing and mature T cells and is tightly regulated in a haplotype- and subset-specific manner. We examined whether Ly-6A/E(low)CD4+ and Ly-6A/E(high)CD4+ T cells comprised functional subsets. Peripheral CD4+ T cells were primed in vitro with Con A in the presence or absence of IL-4 or IFN-gamma, sorted for Ly-6A/E expression, and restimulated to induce lymphokine production.

Role of Ly-6A/E and T cell receptor-zeta for IL-2 production. Phosphatidylinositol-anchored Ly-6A/E antagonizes T cell receptor-mediated IL-2 production by a zeta-independent pathway.

Ly-6A/E molecules were originally implicated in regulation of T cell activation because anti-Ly-6A/E mAb induce IL-2 production. More recently we have shown that anti-Ly-6A/E also inhibits IL-2 production induced by anti-CD3. In the present study we used mutant and transfected cell lines that varied in expression of Ly-6A/E or TCR-zeta to test whether the positive and negative modulations of IL-2 production by anti-Ly-6A/E occur by distinct mechanisms.

Down-regulation of IL-2 production by activation of T cells through Ly-6A/E.

Ly-6A/E molecules are expressed on the surface of T cells and have been shown to function in activation by the capacity of anti-Ly-6A/E mAb to induce T cell hybridomas or normal T cells to produce IL-2. Recent evidence suggests that activation through Ly-6A/E may be linked to the TCR signaling pathway. To further investigate the relationship between Ly-6- and TCR-induced T cell activation, we have examined whether an anti-Ly-6A/E mAb (D7) modulates TCR signaling in vitro.

Regulation of B lymphocyte responses to IL-4 and IFN-gamma by activation through Ly-6A/E molecules.

The Ly-6 family of cell surface molecules has previously been shown to participate in T cell activation. We show that Ly-6A/E proteins also modulated the response of normal B lymphocytes in three separate in vitro assays. First, unfractionated or small resting B cells proliferated when cultured with IFN-gamma, IL-4, and an anti-Ly-6A/E mAb.

Tumor necrosis factor synergistically acts with IFN-gamma to regulate Ly-6A/E expression in T lymphocytes, thymocytes and bone marrow cells.

The Ly-6 alloantigens represent a family of phosphatidylinositol anchored proteins that function in the process of T lymphocyte activation and whose expression are often induced on T and B lymphocytes after activation by mitogens or Ag. Previous studies have shown that the induction of Ly-6 alloantigens in T cells is at least in part due to the action of IFN-alpha/beta or IFN-gamma. In the present report, we have demonstrated that IFN-gamma also induced Ly-6 molecules on B lymphocytes, several B cell tumors, and bone marrow cells.

Expression of Ly-6A/E alloantigens in thymocyte and T-lymphocyte subsets: variability related to the Ly-6a and Ly-6b haplotypes.

We have studied the cellular basis for differential expression of the Ly-6A/E alloantigen on T cells obtained from mice of the Ly-6a (10-20% Ly-6A/E+) and Ly-6b (50-60% Ly-6A/E+) haplotypes. During T-cell ontogeny only a small fraction (less than 12%) of thymocytes expressed Ly-6A/E. By 4 weeks of age adult levels of Ly-6A/E bearing lymphocytes were seen in peripheral lymphoid tissue.

Modification of bronchial blood flow during allergic airway responses.

Ascaris suum antigen effects on mean airflow resistance (RL) and bronchial arterial blood flow (Qbr) were studied in allergic anesthetized sheep with documented airway responses. Qbr was measured with electromagnetic flow probes, and supplemental O2 prevented antigen-induced hypoxemia. Aerosol challenge with this specific antigen increased RL and Qbr significantly.

Indomethacin and FPL-57231 inhibit antigen-induced airway hyperresponsiveness in sheep.

We compared the development of antigen-induced airway hyperresponsiveness (AHR) 24 h after challenge with Ascaris suum antigen in allergic sheep with acute (n = 7) and with dual (n = 7) airway responses and then attempted to modify this AHR. Cholinergic airway responsiveness was determined by measuring the carbachol dose required to increase specific lung resistance (sRL) 150% (i.e.

Differences in airway responsiveness to leukotriene D4 in allergic sheep with and without late bronchial responses.

Allergic sheep respond to inhaled Ascaris suum antigen with either acute and late bronchial obstructions (dual responders) or only acute bronchoconstriction (acute responders). In this study we tested the hypothesis that one factor which may distinguish between these two populations is the difference in sensitivity to a specific mediator of airway anaphylaxis, leukotriene (LT) D4 (a major component of slow reacting substance of anaphylaxis). We postulated that if the hypothesis was correct then dual responders should demonstrate increased airway responses to inhaled LTD4 and that this increased responsiveness should also be reflected by a more severe response to inhaled antigen.

Effects of leukotriene D4 on mucociliary and respiratory function in allergic and nonallergic sheep.

We determined the effect of aerosol challenge with leukotriene D4 (LTD4) on specific lung resistance (sRL) and tracheal mucous velocity (TMV) in conscious sheep with (allergic) and without (nonallergic) Ascaris suum hypersensitivity. In allergic sheep LTD4 in concentrations of 50, 100, and 150 micrograms/ml produced dose-dependent increases in mean sRL by 44 (P = NS), 154 (P less than 0.05), and 233% (P less than 0.

Distribution of serotypes of the Mycobacterium avium-intracellulare-scrofulaceum complex in Georgia.

Cultures of the Mycobacterium avium-intracellulare-scrofulaceum (MAIS) complex, isolated from patients who lived throughout the state of Georgia, were studied using the serotyping scheme of Schaefer. One hundred four (77 per cent) of the 135 isolates tested could be classified into 16 serotypes. The rest were not typable.