scholarly journals CD8+-T-Cell Immunity against Toxoplasma gondii Can Be Induced but Not Maintained in Mice Lacking Conventional CD4+ T Cells

2002 ◽  
Vol 70 (2) ◽  
pp. 434-443 ◽  
Author(s):  
Lori Casciotti ◽  
Kenneth H. Ely ◽  
Martha E. Williams ◽  
Imtiaz A. Khan
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Immune Response ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACT T-cell immunity is critical for survival of hosts infected with Toxoplasma gondii. Among the cells in the T-cell population, CD8+ T cells are considered the major effector cells against this parasite. It is believed that CD4+ T cells may be crucial for induction of the CD8+-T-cell response against T. gondii. In the present study, CD4−/− mice were used to evaluate the role of conventional CD4+ T cells in the immune response against T. gondii infection. CD4−/− mice infected with T. gondii exhibited lower gamma interferon (IFN-γ) messages in the majority of their tissues. As a result, mortality due to a hyperinflammatory response was prevented in these animals. Interestingly, T. gondii infection induced a normal antigen-specific CD8+-T-cell immune response in CD4−/− mice. No difference in generation of precursor cytotoxic T lymphocytes (pCTL) or in IFN-γ production by the CD8+-T-cell populations from the knockout and wild-type animals was observed. However, the mutant mice were not able to sustain CD8+-T-cell immunity. At 180 days after infection, the CD8+-T-cell response in the knockout mice was depressed, as determined by pCTL and IFN-γ assays. Loss of CD8+-T-cell immunity at this time was confirmed by adoptive transfer experiments. Purified CD8+ T cells from CD4−/− donors that had been immunized 180 days earlier failed to protect the recipient mice against a lethal infection. Our study demonstrated that although CD8+-T-cell immunity can be induced in the absence of conventional CD4+ T cells, it cannot be maintained without such cells.

scholarly journals Coinfection with Heligmosomoides polygyrus Fails To Establish CD8+ T-Cell Immunity against Toxoplasma gondii

2008 ◽  
Vol 76 (3) ◽  
pp. 1305-1313 ◽  
Author(s):  
Imtiaz A. Khan ◽  
Rubeena Hakak ◽  
Karen Eberle ◽  
Peter Sayles ◽  
Louis M. Weiss ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
T Cell Immunity ◽  
Cell Immune Response ◽  
Heligmosomoides Polygyrus ◽  
Cell Responses ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACT CD8+ T-cell immunity is important for long-term protection against Toxoplasma gondii infection. However, a Th1 cytokine environment, especially the presence of gamma interferon (IFN-γ), is essential for the development of primary CD8+ T-cell immunity against this obligate intracellular pathogen. Earlier studies from our laboratory have demonstrated that mice lacking optimal IFN-γ levels fail to develop robust CD8+ T-cell immunity against T. gondii. In the present study, induction of primary CD8+ T-cell immune response against T. gondii infection was evaluated in mice infected earlier with Heligmosomoides polygyrus, a gastrointestinal worm known to evoke a polarized Th2 response in the host. In the early stage of T. gondii infection, both CD4 and CD8+ T-cell responses against the parasite were suppressed in the dually infected mice. At the later stages, however, T. gondii-specific CD4+ T-cell immunity recovered, while CD8+ T-cell responses remained low. Unlike in mice infected with T. gondii alone, depletion of CD4+ T cells in the dually infected mice led to reactivation of chronic infection, leading to Toxoplasma-related encephalitis. Our observations strongly suggest that prior infection with a Th2 cytokine-polarizing pathogen can inhibit the development of CD8+ T-cell immune response against T. gondii, thus compromising long-term protection against a protozoan parasite. This is the first study to examine the generation of CD8+ T-cell immune response in a parasitic nematode and protozoan coinfection model that has important implications for infections where a CD8+ T-cell response is critical for host protection and reduced infection pathology.

scholarly journals Lack of Interleukin-12 in p40-Deficient Mice Leads to Poor CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

2010 ◽  
Vol 78 (6) ◽  
pp. 2505-2511 ◽  
Author(s):  
Magali M. Moretto ◽  
Elizabeth M. Lawlor ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Scid Mice ◽  
T Cell Immunity ◽  
Interleukin 12 ◽  
Cell Immune Response ◽  
Encephalitozoon Cuniculi ◽  
Cell Immunity

ABSTRACT A CD8+ T-cell response is critical for protection against Encephalitozoon cuniculi infection. However, the factors responsible for the generation of CD8+ T-cell immunity during E. cuniculi infection and the cytokines involved in this process have not been identified. In the present study, we demonstrated that p40-deficient animals, which are unable to produce interleukin-12 (IL-12), have a serious defect in expansion of the CD8+ T-cell response which compromises the survival of an infected host. Adoptive transfer of CD8+ T cells from immunocompetent donors protected SCID mice infected with E. cuniculi, whereas administration of CD8+ T cells from p40−/− mice failed to protect infected SCID mice. In vitro dendritic cell (DC) cultures from knockout mice pulsed with E. cuniculi spores were unable to develop a robust CD8+ T-cell immune response. Addition of exogenous IL-12 or transfer of CD8+ T cells that were initially primed with DC from p40−/− animals to DC cultures from immunocompetent mice (directly or via transwells) led to optimal expansion of these cells. This IL-12-mediated reinstatement of CD8+ T-effector immunity was independent of gamma interferon (IFN-γ) as addition of antibody to the cultures failed to have an effect. These studies demonstrated that IL-12 plays a predominant role in the expansion of effector CD8+ T-cell immunity against E. cuniculi, which is critical for host survival. These findings are very important for understanding the protective immune mechanisms needed to protect an immunocompromised host against an opportunistic infection and can be extended to other microsporidial pathogens.

scholarly journals The Polyomavirus BK Large T-Antigen-Derived Peptide Elicits an HLA-DR Promiscuous and Polyfunctional CD4+T-Cell Response

2011 ◽  
Vol 18 (5) ◽  
pp. 815-824 ◽  
Author(s):  
Bala Ramaswami ◽  
Iulia Popescu ◽  
Camila Macedo ◽  
Chunqing Luo ◽  
Ron Shapiro ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Antigen ◽  
T Cell Response ◽  
Peptide Sequence ◽  
Large T Antigen ◽  
Hla Dr ◽  
Ifn Γ

ABSTRACTBK virus (BKV) nephropathy and hemorrhagic cystitis are increasingly recognized causes of disease in renal and hematopoietic stem cell transplant recipients, respectively. Functional characterization of the immune response to BKV is important for clinical diagnosis, prognosis, and vaccine design. A peptide mix (PepMix) and overlapping (OPP) or random (RPP) peptide pools derived from BKV large T antigen (LTA) were used to restimulate 14-day-expanded peripheral blood mononuclear cells (PBMC) from 27 healthy control subjects in gamma interferon (IFN-γ)-specific enzyme-linked immunospot (ELISPOT) assays. A T-cell response to LTA PepMix was detected in 15/27 subjects. A response was frequently observed with peptides derived from the helicase domain (9/15 subjects), while the DNA binding and host range domains were immunologically inert (0/15 subjects). For all nine subjects who responded to LTA peptide pools, the immune response could be explained largely by a 15-mer peptide designated P313. P313-specific CD4+T-cell clones demonstrated (i) stringent LTA peptide specificity; (ii) promiscuous recognition in the context of HLA-DR alleles; (iii) cross recognition of homologous peptides from the polyomavirus simian virus 40 (SV40); (iv) an effector memory phenotype, CD107a expression, and intracellular production of IFN-γ and tumor necrosis factor alpha (TNF-α); (v) cytotoxic activity in a chromium release assay; and (vi) the ability to directly present cognate antigen to autologous T cells. In conclusion, T-cell-mediated immunity to BKV in healthy subjects is associated with a polyfunctional population of CD4+T cells with dual T-helper and T-cytotoxic properties. HLA class II promiscuity in antigen presentation makes the targeted LTA peptide sequence a suitable candidate for inclusion in immunotherapy protocols.

scholarly journals Lack of CD4+ T Cells Does Not Affect Induction of CD8+ T-Cell Immunity against Encephalitozoon cuniculi Infection

2000 ◽  
Vol 68 (11) ◽  
pp. 6223-6232 ◽  
Author(s):  
Magali Moretto ◽  
Lori Casciotti ◽  
Brigit Durell ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Mediated Immunity ◽  
Wild Type ◽  
Encephalitozoon Cuniculi ◽  
Cell Immunity ◽  
Mouse Tissues

ABSTRACT Cell-mediated immunity has been reported to play an important role in defense against Encephalitozoon cuniculi infection. Previous studies from our laboratory have underlined the importance of cytotoxic CD8+ T lymphocytes (CTL) in survival of mice infected with E. cuniculi. In the present study, immune response against E. cuniculi infection in CD4+T-cell-deficient mice was evaluated. Similar to resistant wild-type animals, CD4−/− mice were able to resolve E. cuniculi infection even at a very high challenge dose (5 × 107 spores/mouse). Tissues from infected CD4−/− mice did not exhibit higher parasite loads in comparison to the parental wild-type mice. Conversely, at day 21 postinfection, susceptible CD8−/− mice had 1014 times more parasites in the liver compared to control wild-type mice. Induction of the CD8+ T-cell response in CD4−/− mice against E. cuniculi infection was studied. Interestingly, a normal antigen-specific CD8+T-cell response to E. cuniculi infection was observed in CD4−/− mice (precursor proliferation frequency, 1/2.5 × 104 versus 1/104 in wild-type controls). Lack of CD4+ T cells did not alter the magnitude of the antigen-specific CTL response (precursor CTL frequency; 1/1.4 × 104 in CD4−/− mice versus 1/3 × 104 in control mice). Adoptive transfer of immune CD8+ T cells from both CD4−/− and wild-type animals prevented the mortality in CD8−/− mice.E. cuniculi infection thus offers an example of an intracellular parasitic infection where CD8+ T-cell immunity can be induced in the absence of CD4+ T cells.

scholarly journals Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2

2021 ◽  
Author(s):  
Patricia Kaaijk ◽  
Veronica Olivo Pimentel ◽  
Maarten E. Emmelot ◽  
Martien Poelen ◽  
Alper Cevirgel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Immune Memory ◽  
Effector Memory ◽  
Longitudinal Assessment ◽  
Memory T Cell ◽  
Cell Immunity

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. Methods: To determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19. Results: Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-ɣ T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-ɣ T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals. Conclusions: Our data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.

scholarly journals Assessment of T-cell immunity to SARS-CoV-2 in COVID-19 convalescents and vaccinated subjects, using TigraTest® SARS-CoV-2 ELISPOT kit

2021 ◽  
Vol 21 (3) ◽  
pp. 178-192
Author(s):  
D. A. Poteryaev ◽  
S. G. Abbasova ◽  
P. E. Ignatyeva ◽  
O. M. Strizhakova ◽  
S. V. Kolesnik ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Peripheral Blood ◽  
Cell Response ◽  
Human Peripheral Blood ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Cell Immunity

With the onset of the COVID-19 pandemic, a number of molecular-based tests have been developed to diagnose SARS-CoV-2 infection. However, numerous available serological tests lack sufficient sensitivity or specificity. They do not detect specific antibodies in a significant proportion of patients with PCR-confirmed COVID-19. There is evidence that some convalescents have a relatively short-lived humoral immunity. In contrast, a number of publications have shown that T-cell response to human coronaviruses, including SARS-CoV-1, MERS, and SARS-CoV-2, can be strong and long-term. Assessment of T-cell immunity to SARS-CoV-2 is important not only for stratification of risks and identification of potentially protected populations with immunity acquired as a result of previous infection, but also for determining immunogenicity and potential efficacy of vaccines under development. The existing methods of quantitative or semi-quantitative assessment of specific T-cell response are mainly used in scientific research and are not standardised. The aim of the study was to develop and verify experimentally a test kit to be used in a standardised procedure for in vitro determination of T-cells specific to SARS-CoV-2 antigens, in human peripheral blood. Materials and methods: the TigraTest® SARS-CoV-2 kit developed by GENERIUM, which determines the number of T-cells secreting interferon gamma in vitro, was tested in the study. Samples of venous blood of volunteers from three different groups were analysed in the study: presumably healthy volunteers; COVID-19 convalescents; individuals vaccinated against SARS-CoV-2. Results: the authors developed the TigraTest® SARS-CoV-2 kit for in vitro determination of T-cells specific to SARS-CoV-2 antigens in human peripheral blood, demonstrated its specificity and performed preliminary assessment of its sensitivity. The study analysed the range and magnitude of the T-cell response in convalescent and vaccinated individuals. A pronounced T-cell response was also shown in some individuals with no symptoms or with unconfirmed diagnosis. It was discovered that the mean T-cell response to peptides of the spike protein (S-protein) was higher in the vaccinated individuals than in the convalescent patients. A correlation was determined between the severity of the disease and the level of T-cell response. Specific contributions of various groups of antigens to the T-cell response after COVID-19 infection were also determined. Conclusions: the TigraTest® SARS-CoV-2 kit is a specific and sensitive tool for the assessment of T-cell immunity to the SARS-CoV-2 virus, which can also be used for vaccinated individuals. The kit may be used in clinical practice for comprehensive assessment of immunity to SARS-CoV-2.

Association of the level of HER2/neu (HER2) gene amplification in breast cancer and the magnitude of antigen specific T-cell immunity achieved after HER2 vaccination

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3059-3059
Author(s):  
D. Wallace ◽  
M. Disis ◽  
A. Coveler ◽  
D. Higgins ◽  
J. Childs ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
T Cell ◽  
Gene Amplification ◽  
Cell Response ◽  
T Cell Response ◽  
T Cell Immunity ◽  
Her2 Gene ◽  
Cell Immunity ◽  
Her2 Gene Amplification

3059 Background: Studies have demonstrated that the level of HER2 gene amplification in breast cancer, assessed by fluorescence in situ hybridization (FISH), correlates with favorable clinical response after treatment with trastuzumab. We questioned whether HER2 gene amplification impacted the development of HER2-specific T-cell immunity following immunization with a HER2 vaccine. Methods: Patients with HER2+ stage III or IV breast cancer, treated to complete remission or stable bone only disease, were enrolled in one of two concurrent clinical trials of HER2-specific vaccines. Eligibility criteria between the two studies were similar. Patients received either a plasmid DNA-based vaccine encoding the HER2 intracellular domain or a peptide-based vaccine composed of 3 HER2 class II epitopes. Peripheral blood was assessed for HER2-specific T-cell responses by interferon gamma (IFN-g) ELISPOT prior to, immediately after, and 6 months to 1 year after the end of vaccinations. Both immune response and FISH data were available on 31 patients. Results: Correlation of FISH levels to IFN-g spots/well in evaluable patients revealed the level of HER2 gene amplification was not related to the presence of pre-existent HER2-specific T-cell immunity prior to vaccination (p=0.43), the generation of a HER2-specific immune response after vaccination (p=0.35), or the persistence of the HER2-specific T-cell response (p=0.33). However, the magnitude of the T-cell response achieved was less as HER2 gene amplification increased (p=0.05). Conclusions: The level of HER2 gene amplification in the primary tumor can adversely impact the magnitude of HER2-specific T-cell immunity achieved after vaccination. No significant financial relationships to disclose.

scholarly journals The Cytomegalovirus-Specific CD4+ T-Cell Response Expands with Age and Markedly Alters the CD4+ T-Cell Repertoire

2007 ◽  
Vol 81 (14) ◽  
pp. 7759-7765 ◽  
Author(s):  
Batoul Pourgheysari ◽  
Naeem Khan ◽  
Donna Best ◽  
Rachel Bruton ◽  
Laxman Nayak ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Cell Immune Response ◽  
T Cell Repertoire ◽  
Immune Senescence ◽  
Cell Repertoire

ABSTRACT Immune function in the elderly is associated with a number of phenotypic and functional abnormalities, and this phenomenon of immune senescence is associated with increased susceptibility to infection. The immune response to pathogens frequently declines with age, but the CD8+ T-cell response to cytomegalovirus (CMV) is unusual, as it demonstrates a significant expansion over time. Here we have documented the CD4+ T-cell immune response to CMV in healthy donors of different ages. The magnitude of the CMV-specific CD4+ T-cell immune response increases from a mean of 2.2% of the CD4+ T-cell pool in donors below 50 years of age to 4.7% in donors aged over 65 years. In addition, CMV-specific CD4+ T cells in elderly donors demonstrate decreased production of interleukin-2 and less dependence on costimulation. CMV seropositivity is associated with marked changes in the phenotype of the overall CD4+ T-cell repertoire in healthy aged donors, including an increase in CD57+ expression and a decrease in CD28 and CD27 expression, a phenotypic profile characteristic of immune senescence. This memory inflation of CMV-specific CD4+ T cells contributes to evidence that CMV infection may be damaging to immune function in elderly individuals.

scholarly journals NK Cells Help To Induce CD8+-T-Cell Immunity against Toxoplasma gondii in the Absence of CD4+ T Cells

2005 ◽  
Vol 73 (8) ◽  
pp. 4913-4921 ◽  
Author(s):  
Crescent L. Combe ◽  
Tyler J. Curiel ◽  
Magali M. Moretto ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Nk Cells ◽  
Cell Response ◽  
Nk Cell ◽  
Cell Activity ◽  
T Cell Immunity ◽  
Interleukin 12 ◽  
Cell Immunity

ABSTRACT CD8+ T-cell immunity plays an important role in protection against intracellular infections. Earlier studies have shown that CD4+ T-cell help was needed for launching in vivo CD8+ T-cell activity against these pathogens and tumors. However, recently CD4+ T-cell-independent CD8 responses during several microbial infections including those with Toxoplasma gondii have been described, although the mechanism is not understood. We now demonstrate that, in the absence of CD4+ T cells, T. gondii-infected mice exhibit an extended NK cell response, which is mediated by continued interleukin-12 (IL-12) secretion. This prolonged NK cell response is critical for priming parasite-specific CD8+ T-cell immunity. Depletion of NK cells inhibited the generation of CD8+ T-cell immunity in CD4−/− mice. Similarly neutralization of IL-12 reduces NK cell numbers in infected animals and leads to the down-regulation of CD8+ T-cell immunity against T. gondii. Adoptive transfer of NK cells into the IL-12-depleted animals restored their CD8+ T-cell immune response, and animals exhibited reduced mortality. NK cell gamma interferon was essential for cytotoxic T-lymphocyte priming. Our studies for the first time demonstrate that, in the absence of CD4+ T cells, NK cells can play an important role in induction of primary CD8+ T-cell immunity against an intracellular infection. These observations have therapeutic implications for immunocompromised individuals, including those with human immunodeficiency virus infection.

scholarly journals Immunosequencing and epitope mapping reveal substantial preservation of the T cell immune response to Omicron generated by SARS-CoV-2 vaccines

2021 ◽  
Author(s):  
Damon H. May ◽  
Benjamin E. R. Rubin ◽  
Sudeb C. Dalai ◽  
Krishna Patel ◽  
Shahin Shafiani ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cellular Immune Response ◽  
Epitope Mapping ◽  
Protective Efficacy ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Cell Immunity ◽  
Cellular Immune

The Omicron SARS-CoV-2 variant contains 34 mutations in the spike gene likely impacting protective efficacy from vaccines. We evaluated the potential impact of these mutations on the cellular immune response. Combining epitope mapping to SARS-CoV-2 vaccines that we have determined from past experiments along with T cell receptor (TCR) repertoire sequencing from thousands of vaccinated or naturally infected individuals, we estimate the abrogation of the cellular immune response in Omicron. Although 20% of CD4+ T cell epitopes are potentially affected, the loss of immunity mediated by CD4+ T cells is estimated to be slightly above 30% as some of the affected epitopes are relatively more immunogenic. For CD8+ T cells, we estimate a loss of approximately 20%. These reductions in T cell immunity are substantially larger than observed in other widely distributed variants. Combined with the expected substantial loss of neutralization from antibodies, the overall protection provided by SARS-CoV-2 vaccines could be impacted adversely. From analysis of prior variants, the efficacy of vaccines against symptomatic infection has been largely maintained and is strongly correlated with the T cell response but not as strongly with the neutralizing antibody response. We expect the remaining 70% to 80% of on-target T cells induced by SARS-CoV-2 vaccination to reduce morbidity and mortality from infection with Omicron.

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