Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 6 de 6
Filter
Add more filters










Database
Language
Publication year range
2.
J Immunol ; 171(10): 5454-60, 2003 Nov 15.
Article in English | MEDLINE | ID: mdl-14607951

ABSTRACT

The use of cytokines during vaccination, particularly IL-15, is being considered due to the unique ability of IL-15 to enhance the proliferation of memory CD8(+) T cells. However, as homeostatic mechanisms limit excessive lymphocyte expansion, we addressed the consequences of this enhancement of T cell memory by IL-15. Infection of mice with either recombinant Mycobacterium bovis (BCG) expressing IL-15 (BCG-IL-15) or BCG and purified IL-15 resulted in an increased CD44, IL-2Rbeta expression and increased frequency of IFN-gamma-secreting CD8(+) T cells. Surprisingly, the enhancement of memory to concurrent infection by IL-15 exacerbated the attrition of pre-existing memory. Infection of mice with Listeria monocytogenes expressing OVA resulted in potent OVA(257-264)-specific CD8(+) T cell memory, and a challenge of these mice with either BCG-IL-15 or BCG and purified IL-15 resulted in an increased erosion of OVA(257-264)-specific CD8(+) T cell memory, relative to BCG. Enhancement in the erosion of OVA-specific CD8(+) T cell memory by BCG-IL-15 resulted in a consequently greater impairment in protection against a challenge with OVA-expressing tumor cells. We thus raise important questions regarding vaccinations that are aimed at maximizing T cell memory without considering the impact on pre-existing T cell memory.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Down-Regulation/immunology , Immunologic Memory , Interleukin-15/physiology , Up-Regulation/immunology , Adjuvants, Immunologic/biosynthesis , Adjuvants, Immunologic/genetics , Adjuvants, Immunologic/metabolism , Adjuvants, Immunologic/physiology , Animals , CD8-Positive T-Lymphocytes/microbiology , Cell Line, Tumor , Down-Regulation/genetics , Female , Immunity, Cellular/genetics , Immunization, Secondary , Immunologic Memory/genetics , Interleukin-15/biosynthesis , Interleukin-15/genetics , Interleukin-15/metabolism , Listeriosis/genetics , Listeriosis/immunology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mycobacterium bovis/genetics , Mycobacterium bovis/immunology , Mycobacterium bovis/metabolism , Ovalbumin/administration & dosage , Ovalbumin/genetics , Ovalbumin/immunology , Peptide Fragments/administration & dosage , Peptide Fragments/genetics , Peptide Fragments/immunology , Plasmids/metabolism , Tuberculosis/genetics , Tuberculosis/immunology , Up-Regulation/genetics
3.
Infect Immun ; 70(8): 4148-57, 2002 Aug.
Article in English | MEDLINE | ID: mdl-12117923

ABSTRACT

Type 1 T-cell responses against intracellular pathogens play a crucial role in mediating protection. We examined whether the induction of a strong type 1 T-cell response during a chronic bacterial infection influences responses to superantigens capable of inducing acute shock. Intravenous infection of mice with Mycobacterium bovis BCG appeared to induce a progressive anergy towards staphylococcal enterotoxin B (SEB) and towards antigen preparation of BCG (BCG-Ag) itself, based on diminished gamma interferon (IFN-gamma) production by SEB- and BCG-Ag-stimulated splenocytes from infected mice. In contrast to these in vitro results, injection of SEB into BCG-infected mice led to a dramatic increase in the serum IFN-gamma levels and the death of infected but not of control mice. In vitro hyporesponsiveness towards SEB and BCG-Ag occurred only with unfractionated splenocyte cultures, as purified T cells from infected mice produced higher levels of IFN-gamma. Hyporesponsiveness towards SEB and BCG-Ag in unfractionated splenocyte cultures was not due to suppressive antigen-presenting cells (APCs), as APCs from infected mice stimulated higher levels of IFN-gamma from purified T cells. The diminished IFN-gamma levels observed with bulk splenocytes appear to be due to changes in the T-cell-to-APC ratio that result in a decreased proportion of T cells, coupled to reduced proliferative responses and an increased susceptibility of effector T cells to activation-induced cell death in vitro. Our results indicate that the reported phenomena of T-cell anergy during mycobacterial infection may be an in vitro consequence of the development of a strong type 1 response in vivo.


Subject(s)
Enterotoxins/immunology , Mycobacterium bovis/immunology , Shock, Septic/immunology , Spleen/immunology , Superantigens/immunology , Tuberculosis/immunology , Animals , Antigen-Presenting Cells/immunology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cells, Cultured , Disease Susceptibility/immunology , Female , Hyaluronan Receptors , Interferon-gamma/biosynthesis , Mice , Mice, Inbred BALB C , Shock, Septic/complications , Spleen/cytology , Staphylococcus aureus/immunology , Tuberculosis/complications
4.
J Immunol ; 169(3): 1197-206, 2002 Aug 01.
Article in English | MEDLINE | ID: mdl-12133940

ABSTRACT

Induction and maintenance of T cell memory is critical for the control of intracellular pathogens and tumors. Memory T cells seem to require few "maintenance signals," though often such studies are done in the absence of competing immune challenges. Conversely, although attrition of CD8(+) T cell memory has been characterized in heterologous viral models, this is not the case for bacterial infections. In this study, we demonstrate attrition of T cell responses to the intracellular pathogen Listeria monocytogenes (LM) following an immune challenge with a second intracellular bacterium, Mycobacterium bovis (bacillus Calmette-Guérin, BCG). Mice immunized with either LM or recombinant LM (expressing OVA; LM-OVA), develop a potent T cell memory response. This is reflected by peptide-specific CTL, IFN-gamma production, and frequency of IFN-gamma-secreting T cells to native or recombinant LM Ags. However, when the LM-infected mice are subsequently challenged with BCG, there is a marked reduction in the LM-specific T cell responses. These reductions are directly attributable to the effects on CD4(+) and CD8(+) T cells and the data are consistent with a loss of LM-specific T cells, not anergy. Attrition of the Ag (OVA)-specific T cell response is prevented when LM-OVA-immunized mice are challenged with a subsequent heterologous pathogen (BCG) expressing OVA, demonstrating memory T cell dependence on Ag. Although the reduction of the LM-specific T cell response did not impair protection against a subsequent LM rechallenge, for the first time, we show that T cell attrition can result in the reduction of Ag-specific antitumor (B16-OVA) immunity previously established with LM-OVA immunization.


Subject(s)
Antigens, Protozoan/physiology , Bacterial Toxins , Immunologic Memory , Melanoma, Experimental/immunology , T-Lymphocytes/immunology , Animals , Antigen-Presenting Cells/physiology , Cell Line , Female , Heat-Shock Proteins/immunology , Hemolysin Proteins , Immunization , Interferon-gamma/biosynthesis , Lymphocyte Activation , Mice , Mycobacterium bovis/immunology , Ovalbumin/immunology
5.
J Immunol ; 168(11): 5737-45, 2002 Jun 01.
Article in English | MEDLINE | ID: mdl-12023374

ABSTRACT

We evaluated CD8(+) T cell responses against the dominant CTL epitope, OVA(257-264), expressed by an acute (Listeria monocytogenes (LM) OVA) vs a chronic pathogen (Mycobacterium bovis bacillus Calmette-Guérin (BCG) OVA) to reveal the influence on CD8(+) T cell memory and consequent protection against a challenge with OVA-expressing tumor cells. Infection with lower doses of both pathogens resulted in stronger bacterial growth but weaker T cell memory indicating that memory correlates with pathogen dose but not with bacterial expansion. The CD8(+) T cell response induced by LM-OVA was helper T cell-independent and was characterized by a rapid effector response followed by a rapid, but massive, attrition. In contrast, BCG-OVA induced a delayed and weak response that was compensated for by a longer effector phase and reduced attrition. This response was partly dependent on CD4(+) T cells. CD8(+) T cell response induced by BCG-OVA, but not LM-OVA, was highly dependent on pathogen persistence to compensate for the weak initial CD8(+) T cell priming. Despite a stronger initial T cell response with LM-OVA, BCG-OVA provided more effective tumor (B16OVA) control at both local and distal sites due to the induction of a persistently activated acquired, and a more potent innate, immunity.


Subject(s)
CD8-Positive T-Lymphocytes/immunology , Cytotoxicity, Immunologic , Listeria monocytogenes/immunology , Mycobacterium bovis/immunology , Neoplasms, Experimental/prevention & control , Ovalbumin/immunology , Peptide Fragments/immunology , Animals , Female , Immunologic Memory , Listeriosis/immunology , Listeriosis/microbiology , Mice , Mice, Inbred C57BL , Tuberculosis/immunology , Tuberculosis/microbiology
6.
Infect Immun ; 70(4): 1957-64, 2002 Apr.
Article in English | MEDLINE | ID: mdl-11895959

ABSTRACT

Induction of T-cell memory by vaccination ensures long-term protection against pathogens. We determined whether on-going inflammatory responses during vaccination influenced T-cell priming. A preexposure of mice to Mycobacterium bovis BCG impaired their subsequent ability to prime T cells against Listeria monocytogenes. This was characterized by a decrease in L. monocytogenes-specific gamma interferon (IFN-gamma)-secreting CD4(+) and CD8(+) T cells. The intensity of T-cell priming towards L. monocytogenes depended on the extent of L. monocytogenes expansion, and a cessation of this expansion caused by M. bovis BCG-induced inflammation resulted in impairment in T-cell priming. A challenge of M. bovis BCG-infected mice with a higher L. monocytogenes dose increased L. monocytogenes survival and restored T-cell priming towards L. monocytogenes. Impairment in T-cell priming towards L. monocytogenes due to M. bovis BCG-induced inflammation resulted in a compromised protective efficacy in the long term after mice were rechallenged with L. monocytogenes. Preexisting inflammation selectively impaired T-cell priming for replicating immunogens as CD8(+) T-cell response to ovalbumin administered as an inert antigen (ovalbumin-archaeosomes) was enhanced by M. bovis BCG preimmunization, whereas priming towards ovalbumin administered as a live immunogen (L. monocytogenes-ovalbumin) was impaired. Thus, depending on the nature of the immunogen, the presence of prior inflammatory responses may either impede or boost vaccine efficacy.


Subject(s)
Bacterial Toxins , Inflammation/immunology , Mycobacterium bovis/immunology , T-Lymphocytes/immunology , Tuberculosis/immunology , Animals , Female , Heat-Shock Proteins/immunology , Hemolysin Proteins , Immunologic Memory , Listeria monocytogenes/immunology , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL
SELECTION OF CITATIONS
SEARCH DETAIL
...