Increased CD8+-T-Cell Expression and a Type 2 Cytokine Pattern during the Muscular Phase of Trichinella Infection in Humans

ABSTRACT Cell-mediated immunity during the muscular phase of Trichinella infection in humans was studied. Cell proliferation, the phenotypic changes in the T-cell population, and expression and production of cytokines were examined by using peripheral blood mononuclear cells (PBMC) collected at different times postinfection from 10 individuals who had acquired Trichinella spiralis and five individuals who had acquired Trichinella britovi in two distinct outbreaks. T. spiralis and T. britovi crude worm extracts induced proliferation of PBMC from T. spiralis- and T. britovi-infected donors. Cytokine gene expression showed a predominant type 2 pattern for the entire period of infection studied, although gamma interferon (IFN-γ) was expressed. Interleukin-2 (IL-2), IL-5, IL-10, and IFN-γ production was found in PBMC of all donors. There was a good correspondence between the cytokine expression and production patterns. Changes in PBMC composition, with a trend toward an increase in CD8+ lymphocyte counts, were observed.

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Detection of hyperreactive T cells in multiple myeloma by multivalent cross-linking of the CD3/TCR complex [see comments]

Blood ◽

10.1182/blood.v78.7.1770.1770 ◽

1991 ◽

Vol 78 (7) ◽

pp. 1770-1780 ◽

Cited By ~ 33

Author(s):

M Massaia ◽

A Bianchi ◽

C Attisano ◽

S Peola ◽

V Redoglia ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

Interleukin 2 ◽

Normal Subjects ◽

Cross Linking ◽

Peripheral Blood Mononuclear ◽

Hla Dr ◽

Lower Ratio

Abstract Cellular immunity was investigated in 43 patients with multiple myeloma (MM) by assessing 3HTdR uptake induced by monocyte-dependent [CD3 monoclonal antibodies (MoAbs), phytohemagglutinin (PHA)] and monocyte- independent (CD2 MoAbs, ionomycin + phorbolester) stimulations. The former were evaluated in peripheral blood mononuclear cells (PBMNC) and purified T cells; the latter were evaluated in purified T-cell preparations only. MM showed significantly lower PBMNC responses to PHA (P less than .001), soluble OKT3 (CD3) (P = .01), and immobilized OKT3 MoAbs (P = .01). On purification of T cells, MM responses were still defective to soluble T11(2) + T11(3) (CD2) MoAbs (P = .004), phorbol myristate acetate (PMA) plus ionomycin (P less than .001), but significantly higher to plastic-immobilized OKT3 (P = .004). In some MM, 3HTdR uptake, interleukin-2 (IL-2) receptor (CD25) expression, and IL-2 production were as high on stimulation with plastic-immobilized OKT3 as that observed in normal subjects under optimal conditions (ie, plastic-immobilized OKT3 plus accessory signals). CD3 hyperreactivity correlated with the number of CD8+ HLA-DR+ cells in MM T-cell preparations. MM patients with more than 10% CD8+ HLA-DR+ cells had significantly higher responses to immobilized OKT3 (P less than .001), but lower responses to T11(2) plus T11(3) (P = .01), and PMA plus ionomycin (P = .03) than patients with less than 10% CD8+ HLA-DR+ cells. Phenotyping of CD45RA (naive) and CD45R0 (memory) expressions in resting MM T cells showed a lower ratio of CD45RA to CD45R0 in both CD4 (P less than .05) and CD8 (P less than .001) subpopulations. These data indicate that (a) some MM T cells require significantly fewer accessory signals (if any) to express the IL-2 receptor fully, secrete IL-2, and proliferate on multivalent cross-linking of the CD3/TCR complex; and (b) this peculiar state of activation is associated with high HLA-DR expression in CD8+ lymphocytes.

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A 70-Kilodalton Recombinant Heat Shock Protein ofCandida albicans Is Highly Immunogenic and Enhances Systemic Murine Candidiasis

Infection and Immunity ◽

10.1128/iai.66.5.2154-2162.1998 ◽

1998 ◽

Vol 66 (5) ◽

pp. 2154-2162 ◽

Cited By ~ 52

Author(s):

Carla Bromuro ◽

Roberto La Valle ◽

Silvia Sandini ◽

Francesca Urbani ◽

Clara M. Ausiello ◽

...

Keyword(s):

Heat Shock ◽

Heat Shock Protein ◽

Mononuclear Cells ◽

Cell Mediated Immunity ◽

Healthy Human ◽

Peripheral Blood Mononuclear ◽

Necrosis Factor Alpha ◽

Ifn Γ

ABSTRACT The 70-kDa recombinant Candida albicans heat shock protein (CaHsp70) and its 21-kDa C-terminal and 28-kDa N-terminal fragments (CaHsp70-Cter and CaHsp70-Nter, respectively) were studied for their immunogenicity, including proinflammatory cytokine induction in vitro and in vivo, and protection in a murine model of hematogenous candidiasis. The whole protein and its two fragments were strong inducers of both antibody (Ab; immunoglobulin G1 [IgG1] and IgG2b were the prevalent isotypes) and cell-mediated immunity (CMI) responses in mice. CaHsp70 preparations were also recognized as CMI targets by peripheral blood mononuclear cells of healthy human subjects. Inoculation of CaHsp70 preparations into immunized mice induced rapid production of interleukin-6 (IL-6) and tumor necrosis factor alpha, peaking at 2 to 5 h and declining within 24 h. CaHsp70 and CaHsp70-Cter also induced gamma interferon (IFN-γ), IL-12, and IL-10 but not IL-4 production by CD4+ lymphocytes cocultured with splenic accessory cells from nonimmunized mice. In particular, the production of IFN-γ was equal if not superior to that induced in the same cells by whole, heat-inactivated fungal cells or the mitogenic lectin concanavalin A. In immunized mice, however, IL-4 but not IL-12 was produced in addition to IFN-γ upon in vitro stimulation of CD4+ cells with CaHsp70 and CaHsp70-Cter. These animals showed a decreased median survival time compared to nonimmunized mice, and their mortality was strictly associated with organ invasion by fungal hyphae. Their enhanced susceptibility was attributable to the immunization state, as it did not occur in congenitally athymic nude mice, which were unable to raise either Ab or CMI responses to CaHsp70 preparations. Together, our data demonstrate the elevated immunogenicity of CaHsp70, with which, however, no protection against but rather some enhancement of Candida infection seemed to occur in the mouse model used.

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Clinical significance of insulin peptide-specific interferon-γ-related immune responses in ketosis-prone type 2 diabetes

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgab912 ◽

2021 ◽

Author(s):

Atsushi Satomura ◽

Yoichi Oikawa ◽

Akifumi Haisa ◽

Seiya Suzuki ◽

Shunpei Nakanishi ◽

...

Keyword(s):

Type 2 Diabetes ◽

Immune Responses ◽

Elispot Assay ◽

Mononuclear Cells ◽

Cell Function ◽

Β Cell ◽

Peripheral Blood Mononuclear ◽

Β Cell Function ◽

Ifn Γ

Abstract Context Unprovoked A−β+ ketosis-prone type 2 diabetes (KPD) is characterized by the sudden onset of diabetic ketosis/ketoacidosis (DK/DKA) without precipitating factors, negative anti-islet autoantibodies (“A−”), and preservation of β-cell function (“β+”) after recovery from DKA. Although this phenotype often appears with acute hyperglycemia and DK/DKA just like acute-onset type 1 diabetes (AT1D), the involvement of anti-islet immune responses remains unknown. Objective We sought to clarify the immunological role of insulin-associated molecules in unprovoked A−β+ KPD. Methods In this cross-sectional study, blood samples from 75 participants (42 with AT1D and 33 with KPD) were evaluated for interferon (IFN)-γ-secreting peripheral blood mononuclear cells (PBMCs) reactive to four insulin B-chain amino acid 9–23-related peptides (B:9–23rPep) using an enzyme-linked immunospot (ELISpot) assay. Results Overall, 36.4% (12/33) of KPD participants showed positive IFN-γ ELISpot assay results; the positivity rate in KPD was similar to that in AT1D (38.1%; 16/42) and significantly higher than the previously reported rate in type 2 diabetes (8%; 2/25; P < 0.0167). Moreover, B:9–23rPep-specific IFN-γ-producing PBMC frequency was negatively correlated with age and ad lib serum C-peptide levels in all KPD participants and positively correlated with HbA1c level in KPD participants with positive IFN-γ ELISpot results. Conclusions These findings suggest the involvement of B:9–23rPep-specific IFN-γ-related immunoreactivity in the pathophysiology of some unprovoked A−β+ KPD. Moreover, increased immunoreactivity may reflect transiently decreased β-cell function and increased disease activity at the onset of DK/DKA, thereby playing a key role in DK/DKA development in this KPD phenotype.

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Daclizumab reduces CD25 levels on T cells through monocyte-mediated trogocytosis

Multiple Sclerosis Journal ◽

10.1177/1352458513494488 ◽

2013 ◽

Vol 20 (2) ◽

pp. 156-164 ◽

Cited By ~ 16

Author(s):

Y Zhang ◽

M McClellan ◽

L Efros ◽

D Shi ◽

B Bielekova ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

Interleukin 2 ◽

Treg Cells ◽

Activated T Cells ◽

Peripheral Blood Mononuclear ◽

Dependent Relationship ◽

Cell Counts ◽

Humanized Monoclonal Antibody

Daclizumab is a humanized monoclonal antibody that prevents interleukin-2 (IL-2) binding to CD25, blocking IL-2 signaling by cells that require high-affinity IL-2 receptors to mediate IL-2 signaling. The phase 2a CHOICE study evaluating daclizumab as a treatment for multiple sclerosis (MS) included longitudinal analysis of activated T cell counts. Whereas an exposure-dependent relationship was observed between daclizumab and reductions in HLA-DR+-activated T cells, a similar relationship was not observed for reductions in CD25 levels. The objective of this report is to determine the mechanism by which daclizumab reduces CD25 levels on peripheral blood mononuclear cells (PBMCs) using cytometric techniques. Daclizumab reduced T cell CD25 levels through a mechanism that required the daclizumab-Fc domain interaction with Fc receptors (FcR) on monocytes, but not on natural killer (NK) cells, and was unrelated to internalization or cell killing. Activated CD4+ T cells and FoxP3+ Treg cells showed evidence of trogocytosis of the CD25 antigen in the presence of monocytes. A daclizumab variant that retained affinity for CD25 but lacked FcR binding did not induce trogocytosis and was significantly less potent as an inhibitor of IL-2-induced proliferation of PBMCs. In conclusion, Daclizumab-induced monocyte-mediated trogocytosis of CD25 from T cells appears to be an additional mechanism contributing to daclizumab inhibition of IL-2 signaling.

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Lactobacilli and Streptococci Induce Interleukin-12 (IL-12), IL-18, and Gamma Interferon Production in Human Peripheral Blood Mononuclear Cells

Infection and Immunity ◽

10.1128/iai.66.12.6058-6062.1998 ◽

1998 ◽

Vol 66 (12) ◽

pp. 6058-6062 ◽

Cited By ~ 225

Author(s):

Minja Miettinen ◽

Sampsa Matikainen ◽

Jaana Vuopio-Varkila ◽

Jaana Pirhonen ◽

Kari Varkila ◽

...

Keyword(s):

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Protein Production ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Gamma Interferon ◽

Cytokine Gene Expression ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells ◽

Ifn Γ

ABSTRACT Human peripheral blood mononuclear cells (PBMC) were stimulated with three nonpathogenic Lactobacillus strains and with one pathogenic Streptococcus pyogenes strain, and cytokine gene expression and protein production were analyzed. All bacteria strongly induced interleukin-1β (IL-1β), IL-6, and tumor necrosis factor alpha mRNA expression and protein production. S. pyogenes was the most potent inducer of secretion of IL-12 and gamma interferon (IFN-γ), and two of three Lactobacillusstrains induced IL-12 and IFN-γ production. All strains induced IL-18 protein production. IL-10 and IL-4 production was induced weakly and not at all, respectively. Our data show that nonpathogenic lactobacilli and pathogenic streptococci can induce Th1 type cytokines IL-12, IL-18, and IFN-γ in human PBMC.

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Interleukin-2 production and response to interleukin-2 by peripheral blood mononuclear cells from patients after bone marrow transplantation: II. Patients receiving soybean lectin-separated and T cell-depleted bone marrow

Blood ◽

10.1182/blood.v70.5.1595.1595 ◽

1987 ◽

Vol 70 (5) ◽

pp. 1595-1603 ◽

Cited By ~ 23

Author(s):

K Welte ◽

CA Keever ◽

J Levick ◽

MA Bonilla ◽

VJ Merluzzi ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

T Cell ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Mononuclear Cells ◽

Interleukin 2 ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

Abstract The ability of peripheral blood mononuclear cells (PBMC) to produce and respond to interleukin-2 (IL-2) was evaluated in 50 recipients of HLA- identical bone marrow (BM) depleted of mature T cells by soybean agglutination and E rosetting (SBA-E-BM). In contrast to our previous findings in recipients of unfractionated marrow, during weeks 3 to 7 post-SBA-E-BM transplantation (BMT), PBMC from the majority of patients spontaneously released IL-2 into the culture medium. This IL-2 was not produced by Leu-11+ natural killer cells, which were found to be predominant in the circulation at this time, but by T11+, T3+, Ia antigen-bearing T cells. The IL-2 production could be enhanced by coculture with host PBMC frozen before transplant but not by stimulation with mitogenic amounts of OKT3 antibody, thus suggesting an in vivo activation of donor T cells or their precursors by host tissue. Spontaneous IL-2 production was inversely proportional to the number of circulating peripheral blood lymphocytes and ceased after 7 to 8 weeks post-SBA-E-BMT in most of the patients. In patients whose cells had ceased to produce IL-2 spontaneously or never produced this cytokine, neither coculture with host cells nor stimulation with OKT3 antibody thereafter induced IL-2 release through the first year posttransplant. Proliferative responses to exogenous IL-2 after stimulation with OKT3 antibody remained abnormal for up to 6 months post-SBA-E-BMT, unlike the responses of PBMC from recipients of conventional BM, which responded normally by 1 month post-BMT. However, the upregulation of IL- 2 receptor expression by exogenous IL-2 was found to be comparable to normal controls when tested as early as 3 weeks post-SBA-E-BMT. Therefore, the immunologic recovery of proliferative responses to IL-2 and the appearance of cells regulating in vivo activation of T cells appear to be more delayed in patients receiving T cell-depleted BMT. Similar to patients receiving conventional BMT, however, the ability to produce IL-2 after mitogenic stimulation remains depressed for up to 1 year after transplantation.

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Multifunctional Human Immunodeficiency Virus (HIV) Gag-Specific CD8+ T-Cell Responses in Rectal Mucosa and Peripheral Blood Mononuclear Cells during Chronic HIV Type 1 Infection

Journal of Virology ◽

10.1128/jvi.02535-06 ◽

2007 ◽

Vol 81 (11) ◽

pp. 5460-5471 ◽

Cited By ~ 69

Author(s):

J. William Critchfield ◽

Donna Lemongello ◽

Digna H. Walker ◽

Juan C. Garcia ◽

David M. Asmuth ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Mononuclear Cells ◽

Rectal Mucosa ◽

Peripheral Blood Mononuclear ◽

Tnf Α ◽

Immunodeficiency Virus ◽

Ifn Γ ◽

Hiv 1

ABSTRACT The intestinal tract is a lymphocyte-rich site that undergoes severe depletion of memory CD4+ T cells within days of simian immunodeficiency virus or human immunodeficiency virus type 1 (HIV-1) infection. An ensuing influx of virus-specific CD8+ T cells, which persist throughout the chronic phase of infection, has also been documented in the gastrointestinal tract. However, little is known of the functionality of these effector cells or their relationship to the disease course. In this study, we measured CD8+ T-cell responses to HIV-1 peptides in paired rectal and blood samples from chronically infected patients. In both blood and rectum, there was an immunodominant CD8+ T-cell response to HIV Gag compared to Pol and Env (P < 0.01). In contrast, cytomegalovirus pp65 peptides elicited gamma interferon (IFN-γ) secretion strongly in peripheral blood mononuclear cells (PBMC) but weakly in rectal CD8+ T cells (P = 0.015). Upon stimulation with HIV peptides, CD8+ T cells from both sites were capable of mounting complex responses including degranulation (CD107 expression) and IFN-γ and tumor necrosis factor alpha (TNF-α) production. In rectal tissue, CD107 release was frequently coupled with production of IFN-γ or TNF-α. In patients not on antiretroviral therapy, the magnitude of Gag-specific responses, as a percentage of CD8+ T cells, was greater in the rectal mucosa than in PBMC (P = 0.054); however, the breakdown of responding cells into specific functional categories was similar in both sites. These findings demonstrate that rectal CD8+ T cells are capable of robust and varied HIV-1-specific responses and therefore likely play an active role in eliminating infected cells during chronic infection.

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Immune Response to Infection withMycobacterium ulcerans

Infection and Immunity ◽

10.1128/iai.69.3.1704-1707.2001 ◽

2001 ◽

Vol 69 (3) ◽

pp. 1704-1707 ◽

Cited By ~ 78

Author(s):

Travis M. Gooding ◽

Paul D. R. Johnson ◽

Dianne E. Campbell ◽

John A. Hayman ◽

Elizabeth L. Hartland ◽

...

Keyword(s):

Immune Response ◽

Mononuclear Cells ◽

Tuberculin Test ◽

Acid Fast Bacillus ◽

Mycobacterium Ulcerans ◽

Cell Mediated Immunity ◽

Peripheral Blood Mononuclear ◽

T Cell Anergy ◽

Skin Ulcers ◽

Ifn Γ

ABSTRACT Mycobacterium ulcerans is a slow-growing, acid-fast bacillus that causes chronic necrotizing skin ulcers known as Buruli ulcers. Previously reported information on immunity to this mycobacterium is limited. We examined immune responses to M. ulcerans and M. bovis BCG in patients with M. ulcerans disease and in 20 healthy control subjects (10 tuberculin test positive and 10 tuberculin test negative). Cell-mediated immunity was assessed by stimulating peripheral blood mononuclear cells (PBMC) with whole mycobacteria and then measuring PBMC proliferation and the production of gamma interferon (IFN-γ). Humoral immunity was assessed by immunoblotting. PBMC from all subjects showed significantly greater proliferation and IFN-γ production in response to stimulation with living mycobacteria compared with killed cells. However, PBMC from subjects with past or current M. ulcerans disease showed significantly reduced proliferation and production of IFN-γ in response to stimulation with live M. ulcerans or M. bovis than PBMC from healthy, tuberculin test-positive subjects (P < 0.001) and showed results in these assays comparable to those of tuberculin test-negative subjects (P > 0.2). Serum from 9 of 11 patients with M. ulcerans disease, but no control subject, contained antibodies to M. ulcerans. The results indicate that patients with M. ulcerans infection mount an immune response to M. ulcerans as evidenced by antibody production, but they demonstrate profound systemic T-cell anergy to mycobacterial antigens. These findings may explain some of the distinct clinical and pathological features of M. ulcerans-induced disease.

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Cytokine Profiles for Peripheral Blood Lymphocytes from Patients with Active Pulmonary Tuberculosis and Healthy Household Contacts in Response to the 30-Kilodalton Antigen ofMycobacterium tuberculosis

Infection and Immunity ◽

10.1128/iai.66.1.176-180.1998 ◽

1998 ◽

Vol 66 (1) ◽

pp. 176-180 ◽

Cited By ~ 98

Author(s):

Martha Torres ◽

Teresa Herrera ◽

Hector Villareal ◽

Elizabeth A. Rich ◽

Eduardo Sada

Keyword(s):

Peripheral Blood ◽

Mononuclear Cells ◽

Interleukin 2 ◽

Peripheral Blood Lymphocytes ◽

Peripheral Blood Mononuclear ◽

Active Pulmonary Tuberculosis ◽

Household Contacts ◽

Reverse Transcription Pcr ◽

Ifn Γ ◽

Cellular Immune

ABSTRACT Patients with active tuberculosis (TB) have a stronger humoral but a poorer cellular immune response to the secreted 30-kDa antigen (Ag) of Mycobacterium tuberculosis than do healthy household contacts (HHC), who presumably are more protected against disease. The basis for this observation was studied by examining the Th1 (interleukin 2 [IL-2] and gamma interferon [IFN-γ])- and Th2 (IL-10 and IL-4)-type cytokines produced in response to the 30-kDa Ag by peripheral blood mononuclear cells (PBMC) from patients with active pulmonary TB (n = 7) and from HHC who were tuberculin (purified protein derivative) skin test positive (n = 12). Thirty-kilodalton-Ag-stimulated PBMC from TB patients produced significantly lower levels of IFN-γ (none detectable) than did those from HHC (212 ± 73 pg/ml, mean ± standard error) (P < 0.001). Likewise, 30-kDa-Ag-stimulated PBMC from TB patients failed to express IFN-γ mRNA by reverse transcription-PCR, whereas cells from HHC expressed the IFN-γ gene. In contrast, 30-kDa-Ag-stimulated PBMC from TB patients produced significantly higher levels of IL-10 (403 ± 80 pg/ml) than did those from HHC (187 ± 66 pg/ml) (P < 0.013), although cells from both groups expressed the IL-10 gene. IL-2 and IL-4 were not consistently produced, and their genes were not expressed by 30-kDa-Ag-stimulated cells from either TB patients or HHC. After treatment with antituberculous drugs, lymphocytes from four of the seven TB patients proliferated and three of them expressed IFN-γ mRNA in response to the 30-kDa Ag and produced decreased levels of IL-10.

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Cannabinoid type 2 receptor (CB2R) distribution in dermatomyositis skin and peripheral blood mononuclear cells (PBMCs) and in vivo effects of LenabasumTM

Arthritis Research & Therapy ◽

10.1186/s13075-021-02665-x ◽

2022 ◽

Vol 24 (1) ◽

Author(s):

Spandana Maddukuri ◽

Jay Patel ◽

De Anna Diaz ◽

Kristen L. Chen ◽

Maria Wysocka ◽

...

Keyword(s):

Dendritic Cells ◽

Mononuclear Cells ◽

Cytokine Production ◽

Immune Cell ◽

Cell Populations ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells ◽

Ifn Γ

Abstract Background Lenabasum is a cannabinoid type 2 receptor (CB2R) reverse agonist that demonstrates anti-inflammatory effects in vivo and in vitro in dermatomyositis (DM) and is currently being investigated for therapeutic potential. The purpose of our study is to investigate CB2R distribution as well as the effects of lenabasum in DM. Methods Immunohistochemistry staining (IHC) was utilized to examine immune cell and cytokine production changes in lesional DM skin biopsies from lenabasum and placebo-treated patients. CB2R expression in various immune cell populations within DM skin was investigated with image mass cytometry (IMC), whereas flow cytometry elucidated CB2R expression in DM peripheral blood mononuclear cells (PBMCs) as well as cytokine production by CB2R-expressing cell populations. Results After 12 weeks of lenabasum treatment, IHC staining showed that CD4+ T cells, CB2R, IL-31, IFN-γ, and IFN-β cytokines were downregulated. IFN-γ and IFN-β mRNA decreased in lesional DM skin but not in PBMCs. IMC findings revealed that CB2R was upregulated in DM lesional skin compared to HC skin and DM PBMCs (p<0.05). In DM skin, CB2R was upregulated on dendritic cells, B cells, T cells, and macrophages while dendritic cells had the greatest expression in both DM skin and PBMCs (p<0.05). These CB2R+ cells in the skin produce IL-31, IL-4, IFN-γ, and IFN-β. Conclusion Our findings of differential CB2R expression based on location and cell type suggest modes by which lenabasum may exert anti-inflammatory effects in DM and highlights dendritic cells as potential therapeutic targets.

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