Search

Tuberculosis causes 2 million deaths per year, yet in most cases the immune response successfully contains the infection and prevents disease outbreak. Induced lymphoid structures associated with pulmonary granuloma are observed during tuberculosis in both humans and mice and could orchestrate host defense. To investigate whether granuloma perform lymphoid functions, mice lacking secondary lymphoid organs (SLO) were infected with Mycobacterium tuberculosis (MTB). As in WT mice, granuloma developed, exponential growth of MTB was controlled, and antigen-specific T-cell responses including memory T cells were generated in the absence of SLO. Moreover, adoptively transferred T cells were primed locally in lungs in a granuloma-dependent manner. T-cell activation was delayed in the absence of SLO, but resulted in a normal development program including protective subsets and functional recall responses that protected mice against secondary MTB infection. Our data demonstrate that protective immune responses can be generated independently of SLO during MTB infection and implicate local pulmonary T-cell priming as a mechanism contributing to host defense.

N-acetyl-L-cysteine (NAC) is a thiol antioxidant that stimulates glutathione synthesis in cells. Several studies indicate that NAC possesses immunomodulatory properties in vitro, but both inhibitory and activating effects on immunity have been reported. We observed that allogeneic stem cell transplantation (ASCT) patients who were randomized to receive NAC 100 mg/kg/day (n=73) had an increased prevalence of grade II-V acute graft-versus-host disease (GvHD) compared to patients who did not receive NAC (n=87), indicating that NAC has an immunostimulatory effect in vivo. When studying the effect of NAC on T-cell-mediated immunity in vitro, we found that moderate levels of NAC (0.4-3.2 mM) increased alloantigen-induced proliferation, expression of activation markers CD25 and CD71 on T cells, and production of IFN-γ and IL-10. In contrast, high concentrations of NAC (12.5-50 mM) were suppressive, which may explain previously conflicting data. NAC did not cause an increase in expression of CD86, CD80, and CD83 on mature DCs at any concentration, whereas high concentrations suppressed DC maturation. Furthermore, T cells exposed to suppressive concentrations of NAC in a primary stimulation were highly responsive when re-stimulated in the absence of NAC. To conclude, NAC appears to increase acute GvHD and has an immunostimulatory effect on alloantigen-specific T cells.

Low responsiveness of DBA/1 mice in T cell-mediated cytotoxicity against the DBA/2 mastocytoma P-815 (H-2d) is genetically controlled and inherited as a recessive trait. For an analysis of the humoral anti-H-2d response of DBA/1 mice after immunization with P-815 mastocytoma cells both complement-dependent lysis (CDL) and the cytotoxicity inhibition assay (CIA) were used to demonstrate antibodies. Both assays show that DBA/1 mice are unable to produce anti-H-2d antibodies in a secondary response. Even high doses of immunizing cells give only a weak response. The response is fully recovered upon allogeneic interaction. A transient primary anti-H-2d activity can be found in the CIA but not by CDL. The data show that the genetically controlled determinant-specific defect in T cell-mediated cytotoxicity among DBA/1 mice has its correlate in a blockade of memory formation or expression in the humoral anti-H-2d response.

Previous reports have demonstrated that adult C 57 BL/6 mice infected with murine sarcoma virus (MSV) develop a strong cell-mediated immune response against Friend, Moloney, Rauscher virus-induced type-specific (FMR) antigens and reject their tumors. To demonstrate a possible role for auto-anti-MSV T blasts, syngeneic C 57 BL/6 mice were immunized with highly enriched anti-FMR cytolytic T cells. One of 3 pools of these autoimmune T cells prepared from 12 surviving immunized mice (a) inhibited specifically the in vitro anti-MSV cytolysis generation and (b) enhanced drastically the MSV tumor growth in vivo. The possibility for such an immunization procedure to induce anti-idiotype T cells, the repeatability of this effect and the relationship of the suppressor cells with antigen-specific suppressor cells and other components of the anti-MSV immune response are discussed.

We investigated whether recognition per se of cell surface antigens by lymphocytes is both necessary and sufficient to trigger sensitization of T cells. We assayed sensitization of normal rat lymphocytes against monolayers of mouse fibroblasts by measuring the acquisition of cytotoxicity against target monolayers syngeneic to the sensitizing monolayer, following 5 days of culturing on living or glutaraldehyde-fixed fibroblasts. Monolayers of either living or glutaraldehyde-treated fibroblasts were used as cellular immunoadsorbents to assay recognition. Glutaraldehyde treatment of mouse fibroblasts did not seem to alter the cell surface antigens detectable by alloantibodies. Yet, rat lymphocytes cultured on such monolayers did not undergo sensitization. This was not due to the lack of feeder effect by the glutaraldehyde-fixed monolayers, since the addition of living rat fibroblasts, which sustained the survival of the lymphocytes, did not result in sensitization. Not even when living fibroblasts were added to syngeneic fixed monolayers did sensitization of the rat lymphocytes against the monolayer cells occur. Yet, addition of living fibroblasts to fixed allogeneic monolayers resulted in sensitization against the living fibroblasts, but not against the fixed cells. To test whether lymphocytes recognize surface antigens of glutaraldehyde-treated monolayers, the capacity of the latter to specifically adsorb lymphocytes possessing receptors for the fibroblast antigen was measured. The nonadhering rat lymphocytes, seeded on glutaraldehyde-treated C3H fibroblasts, lost their capacity to become sensitized against fresh C3H cells, but retained their capacity to react against BALB/c fibroblasts. Recognition of C3H antigen did take place, yet this was not sufficient to trigger sensitization. Thus, rat lymphocytes seem to recognize the antigens of fixed monolayers, but cannot respond to them.

We compared induction of sensitization in the mixed lymphocyte reaction (MLR) and in a mouse anti-fibroblast reaction. Our study demonstrated that induction processes in these two reactions, both known to be T cell-mediated reactions, are governed by different factors. Moreover, these two reactions interact with each other and this interaction is manifested by the ability of a MLR occurring during the sensitization phase of the anti-fibroblast reaction to enhance specific cytolysis measured during the effector phase. This helper effect appears to be immunologically nonspecific, since it can be obtained by the use of third party, antigenically unrelated lymphocytes as stimulator cells in the MLR.