scholarly journals Essential Roles for CD8+ T Cells and Gamma Interferon in Protection of Mice against Retrovirus-Induced Immunosuppression

2002 ◽  
Vol 76 (1) ◽  
pp. 450-454 ◽  
Author(s):  
Ulf Dittmer ◽  
Brent Race ◽  
Karin E. Peterson ◽  
Ingunn M. Stromnes ◽  
Ronald J. Messer ◽  
...  
Keyword(s):  
T Cells ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Antibody Responses ◽  
Mhc I ◽  
Mhc Genes ◽  
Histocompatibility Complex ◽  
Immunosuppressive Cytokine ◽  
Ifn Γ

ABSTRACT It is known that both animal and human retroviruses typically cause immunosuppression in their respective hosts, but the mechanisms by which this occurs are poorly understood. The present study uses Friend virus (FV) infections of mice as a model to determine how major histocompatibility complex (MHC) genes influence immunosuppression. Previously, MHC-I genes were shown to influence antibody responses to potent antigenic challenges given during acute FV infection. The mapping of an immune response to an MHC-I gene implicated CD8+ T cells in the mechanism, so we directly tested for their role by using in vivo CD8+ T-cell depletions. Mice resistant to FV-induced immunosuppression became susceptible when they were depleted of CD8+ T cells. Resistance also required gamma interferon (IFN-γ), as in vivo neutralization of IFN-γ converted mice from a resistant to susceptible phenotype. On the other hand, susceptibility to FV-induced immunosuppression was dependent on the immunosuppressive cytokine, interleukin-10 (IL-10), as antibody responses were restored in susceptible mice when IL-10 function was blocked in vivo. Thus, FV-induced immunosuppression of antibody responses involves complex mechanisms controlled at least in part by CD8+ T cells.

scholarly journals Major Histocompatibility Complex Class I Gene Controls the Generation of Gamma Interferon-Producing CD4+and CD8+ T Cells Important for Recovery from Friend Retrovirus-Induced Leukemia

2000 ◽  
Vol 74 (11) ◽  
pp. 5363-5367 ◽  
Author(s):  
Karin E. Peterson ◽  
Michihiro Iwashiro ◽  
Kim J. Hasenkrug ◽  
Bruce Chesebro
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Mhc Class I ◽  
Gamma Interferon ◽  
Class I ◽  
Major Histocompatibility ◽  
Cell Responses ◽  
Histocompatibility Complex ◽  
Ifn Γ

ABSTRACT Recovery from leukemia induced by Friend virus complex (FV) requires strong CD4+ helper, CD8+ cytotoxic T-lymphocyte, and B-cell responses. The development of these immune responses is dependent on the major histocompatibility complex (MHC) (H-2) genotype of the mouse. InH-2b/b mice, which spontaneously recover from FV-induced erythroleukemia, neutralization of gamma interferon (IFN-γ) in vivo inhibited recovery, which indicated that IFN-γ was a necessary component of the immune response to FV. Furthermore, inH-2b/b mice, high numbers of IFN-γ-producing cells were detected after FV infection, whereas inH-2a/b mice, which have a low-recovery phenotype, only low numbers of IFN-γ-producing cells were detected. Similarly, H-2bm14/b mice, which cannot recover from FV infection due to a point mutation in one allele of theH-2Db gene, also had low numbers of IFN-γ-producing T cells. Surprisingly, this effect was observed for both CD8+ and CD4+ T cells. These findings reveal a novel influence of MHC class I genes on CD4+T-cell responses to viral infection. Furthermore, the influence of MHC class I genotype on the generation of both IFN-γ-producing CD4+ and CD8+ T cells helps explain the major impact of the H-2D gene on recovery from FV disease.

Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3094-3101 ◽  
Author(s):  
Premlata Shankar ◽  
Melissa Russo ◽  
Brooke Harnisch ◽  
Mark Patterson ◽  
Paul Skolnik ◽  
...  
Keyword(s):  
T Cells ◽  
Reverse Transcriptase ◽  
Cd8 T Cells ◽  
Culture Medium ◽  
Significant Proportion ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Mixed Pattern

Abstract The functional status of circulating human immunodeficiency (HIV)-specific CD8 T cells in chronically infected subjects was evaluated. By flow cytometry, only 5 of 7 subjects had detectable CD8 T cells that produced IFN-γ after stimulation with HIV-infected primary CD4 T cells. In 2 subjects, the frequency of IFN-γ–producing cells increased 4-fold when IL-2 was added to the culture medium; in another subject, IFN-γ–producing cells could be detected only after IL-2 was added. IFN-γ–producing cells ranged from 0.4% to 3% of CD8 T cells. Major histocompatibility complex–peptide tetramer staining, which identifies antigen-specific T cells irrespective of function, was used to evaluate the proportion of HIV-specific CD8 T cells that may be nonfunctional in vivo. CD8 T cells binding to tetramers complexed to HIV gag epitope SLYNTVATL and reverse transcriptase epitope YTAFTIPSI were identified in 9 of 15 and 5 of 12 HLA-A2–expressing seropositive subjects at frequencies of 0.1% to 1.1% and 0.1 to 0.7%, respectively. Freshly isolated tetramer-positive cells expressed a mixed pattern of memory and effector markers. On average, IFN-γ was produced by less than 25% of tetramer-positive CD8 T cells after stimulation with the relevant gag or reverse transcriptase peptide. In all subjects tested, freshly isolated CD8 T cells were not cytolytic against peptide-pulsed B lymphoblastoid cell line or primary HIV-infected CD4 T-cell targets. Exposure to IL-2 enhanced the cytotoxicity of CD8 T cells against primary HIV-infected CD4 targets in 2 of 2 subjects tested. These results suggest that a significant proportion of HIV-specific CD8 T cells may be functionally compromised in vivo and that some function can be restored by exposure to IL-2.

scholarly journals The Role of Interleukin-10 (IL-10) in IL-15–Mediated T-Cell Responses

Blood ◽  
1997 ◽  
Vol 90 (11) ◽  
pp. 4513-4521 ◽  
Author(s):  
Dieter Körholz ◽  
Ursula Banning ◽  
Halvard Bönig ◽  
Markus Grewe ◽  
Marion Schneider ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Interleukin 10 ◽  
T Cell Proliferation ◽  
Cell Production ◽  
Cd25 Expression ◽  
Tnf Α ◽  
Ifn Γ

Abstract Interleukin-15 (IL-15) is a potent T-cell stimulating factor, which has recently been used for pre-clinical in vivo immunotherapy. Here, the IL-15 effect on CD3-stimulated peripheral human T cells was investigated. IL-15 induced a significant T-cell proliferation and upregulated CD25 expression. IL-15 significantly enhanced T-cell production of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and IL-10. Between 10- and 100-fold greater concentrations of IL-15 were necessary to reach a biological effect equivalent to that of IL-2. Blockade of IL-2 binding to the high-affinity IL-2 receptor did not affect the IL-15 effects, suggesting that IL-15 did not act by inducing endogenous IL-2. Exogenously administered IL-10 significantly reduced the IL-15 and IL-2–mediated IFN-γ and TNF-α production, whereas T-cell proliferation and CD25 expression were not affected. The inhibitory effects of exogenously administered IL-10 on T-cell cytokine production appeared indirect, and are likely secondary to decreased IL-12 production by accessory cells. Inhibition of endogenous IL-10 binding to the IL-10 receptor significantly increased IFN-γ and TNF-α release from T cells. These data suggest that endogenous IL-10 can regulate activated T-cell production of IFN-γ and TNF-α via a paracrine negative feedback loop. The observations of this study could be of relevance for the therapeutic use of IL-15 in vivo.

scholarly journals Interleukin-10 Has Different Effects on Proliferation of Listeria monocytogenes in Livers and Spleens of Mice

2000 ◽  
Vol 68 (8) ◽  
pp. 4666-4672 ◽  
Author(s):  
Janneke N. Samsom ◽  
Akke Annema ◽  
Minke F. Geertsma ◽  
Jan A. M. Langermans ◽  
Paul H. P. Groeneveld ◽  
...  
Keyword(s):  
T Cells ◽  
Listeria Monocytogenes ◽  
Primary Infection ◽  
Secondary Infection ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Ifn Γ ◽  
Number Of Bacteria

ABSTRACT The aim of this study was to investigate the effect of interleukin-10 (IL-10) on the course of Listeria monocytogenes infection in naive and immune mice. Treatment with IL-10 during the course of a primary infection significantly decreased the number of bacteria in the spleen and did not affect the number in the liver. During a secondary infection in immune mice treated with IL-10, the number of bacteria was significantly lower in the spleen but significantly higher in the liver in comparison to mock-treated immune mice. IL-10 treatment during a primary Listeria infection decreased the concentration of gamma interferon (IFN-γ) in plasma and the toxoplasmastatic activity of macrophages, whereas it increased the percentage of mildly CD3-positive T cells in the spleen. During a secondary infection, the concentration of IFN-γ in plasma was decreased on day 1 but remained unaffected during later days of infection. From these results, we conclude that IL-10 has different effects on the proliferation of L. monocytogenes in the spleen and liver during primary and secondary Listeriainfections.

Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3094-3101 ◽  
Author(s):  
Premlata Shankar ◽  
Melissa Russo ◽  
Brooke Harnisch ◽  
Mark Patterson ◽  
Paul Skolnik ◽  
...  
Keyword(s):  
T Cells ◽  
Reverse Transcriptase ◽  
Cd8 T Cells ◽  
Culture Medium ◽  
Significant Proportion ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Ifn Γ ◽  
Mixed Pattern

The functional status of circulating human immunodeficiency (HIV)-specific CD8 T cells in chronically infected subjects was evaluated. By flow cytometry, only 5 of 7 subjects had detectable CD8 T cells that produced IFN-γ after stimulation with HIV-infected primary CD4 T cells. In 2 subjects, the frequency of IFN-γ–producing cells increased 4-fold when IL-2 was added to the culture medium; in another subject, IFN-γ–producing cells could be detected only after IL-2 was added. IFN-γ–producing cells ranged from 0.4% to 3% of CD8 T cells. Major histocompatibility complex–peptide tetramer staining, which identifies antigen-specific T cells irrespective of function, was used to evaluate the proportion of HIV-specific CD8 T cells that may be nonfunctional in vivo. CD8 T cells binding to tetramers complexed to HIV gag epitope SLYNTVATL and reverse transcriptase epitope YTAFTIPSI were identified in 9 of 15 and 5 of 12 HLA-A2–expressing seropositive subjects at frequencies of 0.1% to 1.1% and 0.1 to 0.7%, respectively. Freshly isolated tetramer-positive cells expressed a mixed pattern of memory and effector markers. On average, IFN-γ was produced by less than 25% of tetramer-positive CD8 T cells after stimulation with the relevant gag or reverse transcriptase peptide. In all subjects tested, freshly isolated CD8 T cells were not cytolytic against peptide-pulsed B lymphoblastoid cell line or primary HIV-infected CD4 T-cell targets. Exposure to IL-2 enhanced the cytotoxicity of CD8 T cells against primary HIV-infected CD4 targets in 2 of 2 subjects tested. These results suggest that a significant proportion of HIV-specific CD8 T cells may be functionally compromised in vivo and that some function can be restored by exposure to IL-2.

scholarly journals Survival of Salmonella enterica Serovar Typhimurium within Late Endosomal-Lysosomal Compartments of B Lymphocytes Is Associated with the Inability To Use the Vacuolar Alternative Major Histocompatibility Complex Class I Antigen-Processing Pathway

2005 ◽  
Vol 73 (7) ◽  
pp. 3937-3944 ◽  
Author(s):  
Roberto Rosales-Reyes ◽  
Celia Alpuche-Aranda ◽  
María de la Luz Ramírez-Aguilar ◽  
Angel Denisse Castro-Eguiluz ◽  
Vianney Ortiz-Navarrete
Keyword(s):  
B Lymphocytes ◽  
Salmonella Enterica ◽  
Antigen Processing ◽  
Macrophage Cell ◽  
Mhc I ◽  
Lysosomal Compartment ◽  
Histocompatibility Complex ◽  
Serovar Typhimurium ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ)-activated macrophages use an alternative processing mechanism to present Salmonella antigens to CD8+ T lymphocytes. This pathway involves processing of antigen in a vacuolar compartment followed by secretion and loading of antigenic peptides to major histocompatibility complex class I (MHC-I) molecules on macrophage cell surface and bystander cells. In this study, we have shown that B lymphocytes are not able to process Salmonella antigens using this alternative pathway. This is due to differences in Salmonella enterica serovar Typhimurium-containing vacuoles (SCV) when comparing late endosomal-lysosomal processing compartments in B lymphocytes to those in macrophages. The IFN-γ-activated IC21 macrophage cell line and A-20 B-cell line were infected with live or dead Salmonella enterica serovar Typhimurium. The SCV in B cells were in a late endosomal-lysosomal compartment, whereas SCV in macrophages were remodeled to a noncharacteristic late endosomal-lysosomal compartment over time. Despite the difference in SCV within macrophages and B lymphocytes, S. enterica serovar Typhimurium survives more efficiently within the IFN-γ-activated B cells than in activated macrophage cell lines. Similar results were found during in vivo acute infection. We determined that a lack of remodeling of late endosomal-lysosomal compartments by live Salmonella infection in B lymphocytes is associated with the inability to use the alternative MHC-I antigen-processing pathway, providing a survival advantage to the bacterium. Our data also suggest that the B lymphocyte late endosome-lysosome environment allows the expression of Salmonella virulence mechanisms favoring B lymphocytes in addition to macrophages and dendritic cells as a reservoir during in vivo infection.

scholarly journals Differences in Gamma Interferon Production In Vitro Predict the Pace of the In Vivo Response to Leishmania amazonensis in Healthy Volunteers

2001 ◽  
Vol 69 (12) ◽  
pp. 7453-7460 ◽  
Author(s):  
M. M. L. Pompeu ◽  
C. Brodskyn ◽  
M. J. Teixeira ◽  
J. Clarêncio ◽  
J. Van Weyenberg ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Leishmania Amazonensis ◽  
Cell Mediated Immunity ◽  
Peripheral Blood Mononuclear ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

ABSTRACT The initial encounter of Leishmania cells and cells from the immune system is fundamentally important in the outcome of infection and determines disease development or resistance. We evaluated the anti-Leishmania amazonensis response of naive volunteers by using an in vitro priming (IVP) system and comparing the responses following in vivo vaccination against the same parasite. In vitro stimulation allowed us to distinguish two groups of individuals, those who produced small amounts of gamma interferon (IFN-γ) (n = 16) (low producers) and those who produced large amounts of this cytokine (n = 16) (high producers). IFN-γ production was proportional to tumor necrosis factor alpha and interleukin 10 (IL-10) levels but did not correlate with IL-5 production. Volunteers who produced small amounts of IFN-γ in vitro remained low producers 40 days after vaccination, whereas high producers exhibited increased IFN-γ production. However, 6 months after vaccination, all individuals tested produced similarly high levels of IFN-γ upon stimulation of their peripheral blood mononuclear cells with Leishmania promastigotes, indicating that low in vitro producers respond slowly in vivo to vaccination. In high IFN-γ producers there was an increased frequency of activated CD8+ T cells both in vitro and in vivo compared to the frequency in low producers, and such cells were positive for IFN-γ as determined by intracellular staining. Such findings suggest that IVP responses can be used to predict the pace of postvaccination responses of test volunteers. Although all vaccinated individuals eventually have a potent anti-Leishmania cell-mediated immunity (CMI) response, a delay in mounting the CMI response may influence resistance against leishmaniasis.

scholarly journals LACK-Specific CD4+ T Cells That Induce Gamma Interferon Production in Patients with Localized Cutaneous Leishmaniasis during an Early Stage of Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 3122-3129 ◽  
Author(s):  
Eliane Bourreau ◽  
Ghislaine Prévot ◽  
Jacques Gardon ◽  
Roger Pradinaud ◽  
Hitoshi Hasagewa ◽  
...  
Keyword(s):  
T Cells ◽  
Early Stage ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Effector Memory ◽  
Cellular Source ◽  
Effector Memory Cells ◽  
Ifn Γ

ABSTRACT The profile of cytokines induced by soluble leishmania antigen (SLA) and the Leishmania homologue of the mammalian receptor for activated C kinase (LACK), a candidate vaccine against leishmaniasis, and the cellular source of the cytokines produced in response to these antigens were analyzed in patients infected with Leishmania guyanensis. Gamma interferon (IFN-γ) and interleukin-10 (IL-10) were produced in response to LACK. Although LACK-specific CD4+ cells producing IFN-γ were isolated only during the early phase of infection (less than 30 days following the onset of infection), cells producing IL-10 in response to LACK were detected in all patients. CD4+ T cells producing IFN-γ and IL-13 were produced in response to SLA in all patients. SLA- and LACK-specific T cells are effector memory cells, as they are CD45RA− CCR7− CD4+ T cells. CD4+ T cells producing IFN-γ are CD62L−, and CD4+ T cells producing IL-10 are CD62L+, indicating that these cells have different tissue-homing capacities. These findings show that SLA and LACK induce both type 1 (IFN-γ) and type 2 (IL-10 or IL-13) cell responses.

scholarly journals An Important Role for Major Histocompatibility Complex Class I-Restricted T Cells, and a Limited Role for Gamma Interferon, in Protection of Mice against Lethal Herpes Simplex Virus Infection

1999 ◽  
Vol 73 (3) ◽  
pp. 2058-2063 ◽  
Author(s):  
Ai-Xuan Holterman ◽  
Kathleen Rogers ◽  
Kurt Edelmann ◽  
David M. Koelle ◽  
Lawrence Corey ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Mhc Class I ◽  
Gamma Interferon ◽  
Class I ◽  
Histocompatibility Complex ◽  
Ifn Γ ◽  
Simplex Virus

ABSTRACT Herpes simplex virus (HSV) inhibits major histocompatibility complex (MHC) class I expression in infected cells and does so much more efficiently in human cells than in murine cells. Given this difference, if MHC class I-restricted T cells do not play an important role in protection of mice from HSV, an important role for these cells in humans would be unlikely. However, the contribution of MHC class I-restricted T cells to the control of HSV infection in mice remains unclear. Further, the mechanisms by which these cells may act to control infection, particularly in the nervous system, are not well understood, though a role for gamma interferon (IFN-γ) has been proposed. To address the roles of MHC class I and of IFN-γ, C57BL/6 mice deficient in MHC class I expression (β2 microglobulin knockout [β2KO] mice), in IFN-γ expression (IFN-γKO mice), or in both (IFN-γKO/β2KO mice) were infected with HSV by footpad inoculation. β2KO mice were markedly compromised in their ability to control infection, as indicated by increased lethality and higher concentrations of virus in the feet and spinal ganglia. In contrast, IFN-γ appeared to play at most a limited role in viral clearance. The results suggest that MHC class I-restricted T cells play an important role in protection of mice against neuroinvasive HSV infection and do so largely by mechanisms other than the production of IFN-γ.

scholarly journals Protection against Mycobacterium tuberculosisInfection by CD8+ T Cells Requires the Production of Gamma Interferon

1998 ◽  
Vol 66 (2) ◽  
pp. 830-834 ◽  
Author(s):  
Ricardo E. Tascon ◽  
Evangelos Stavropoulos ◽  
Katalin V. Lukacs ◽  
M. Joseph Colston
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Protective Immunity ◽  
Gamma Interferon ◽  
Cell Populations ◽  
Athymic Mice ◽  
Histocompatibility Complex ◽  
Cd8 Cell ◽  
Ifn Γ

ABSTRACT The role of CD8 T cells in controlling Mycobacterium tuberculosis infections in mice was confirmed by comparing the levels of growth of the organism in control, major histocompatibility complex class II knockout, and athymic mice and by transferring T-cell populations into athymic mice. By using donor mice which were incapable of making gamma interferon (IFN-γ), it was shown that IFN-γ production was essential for CD8 cell mediation of protective immunity against M. tuberculosis.

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