CD28 Costimulation Is Required for the Expression of T-Cell-Dependent Cell-Mediated Immunity against Blood-Stage Plasmodium chabaudi Malaria Parasites

ABSTRACT Mice suppress the parasitemia of acute blood-stage Plasmodium chabaudi malaria by an antibody- or T-cell-dependent cell-mediated mechanism of immunity (AMI and CMI, respectively) or by both mechanisms. To determine whether CD28 costimulation is required for expression of these polar immune responses, we first compared the time courses of P. chabaudi malaria in CD28-deficient (CD28−/−) and CD28-intact (CD28+/+) mice. Acute infections in both knockout (KO) and control mice followed similar time courses, with the period of descending parasitemia being prolonged ∼2 weeks in KO mice followed by intermittent low-grade chronic parasitemia. Infected CD28−/− mice produced primarily the immunoglobulin M antibody, which upon passive transfer provided partial protection against P. chabaudi challenge, suggesting that the elimination of blood-stage parasites by CD28−/− mice was achieved by AMI. To determine whether CD28−/− costimulation is required for the expression of CMI against the parasite, we compared the time courses of parasitemia in B-cell-deficient double-KO (JH −/− × CD28−/−) mice and control (JH −/− × CD28+/+) mice. Whereas control mice suppressed parasitemia to subpatent levels within ∼2 weeks postinoculation, double-KO mice developed high levels of parasitemia of long-lasting duration. Although not required for the suppression of acute P. chabaudi parasitemia by AMI, CD28 costimulation is essential for the elimination of blood-stage parasites by CMI.

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Splenic γδ T Cells Regulated by CD4+ T Cells Are Required To Control Chronic Plasmodium chabaudi Malaria in the B-Cell-Deficient Mouse

Infection and Immunity ◽

10.1128/iai.74.5.2717-2725.2006 ◽

2006 ◽

Vol 74 (5) ◽

pp. 2717-2725 ◽

Cited By ~ 11

Author(s):

Henri C. van der Heyde ◽

Joan M. Batchelder ◽

Matyas Sandor ◽

William P. Weidanz

Keyword(s):

T Cells ◽

T Cell ◽

Γδ T Cells ◽

Cell Receptor ◽

Blood Stage ◽

Cell Mediated Immunity ◽

Γδ T Cell ◽

Plasmodium Chabaudi ◽

Antibody Treatment ◽

Time Courses

ABSTRACT Little is known about the function and regulation of splenic γδ T cells during chronic Plasmodium chabaudi malaria. The splenic γδ T-cell population continues to expand, reaching levels equal to 4 times the number of splenocytes in an uninfected mouse. Splenic γδ T cells from JH −/− mice with chronic malaria expressed Vγ1+ or Vδ4+ in the same ratio as uninfected controls with Vγ1 cells dominating, but the Vγ2 ratio declined about twofold. γδ T cells from G8 mice specific for the TL antigen increased only 2-fold in number, compared with 10-fold in BALB/c controls, but G8 γδ T cells failed to express the B220 activation marker. Elimination of the parasite by drug treatment caused a slow depletion in the number of splenic γδ, CD4+, and CD8+ T cells. Following challenge, drug-cured JH −/− mice exhibited nearly identical parasitemia time courses as naïve controls. Depletion of either CD4+ T cells or γδ T cells from chronically infected JH −/− mice by monoclonal antibody treatment resulted in an immediate and significant (P < 0.05) exacerbation of parasitemia coupled with a marked decrease in splenic γδ T-cell numbers. The number of CD4+ T cells, in contrast, did not decrease in mice after anti-T-cell receptor γδ treatment. The results indicate that cell-mediated immunity against blood-stage malarial parasites during chronic malaria (i) requires the continued presence of blood-stage parasites to remain functional, (ii) is dependent upon both γδ T cells and CD4+ T cells, and (iii) lacks immunological memory.

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γδ T Cells but Not NK Cells Are Essential for Cell-Mediated Immunity against Plasmodium chabaudi Malaria

Infection and Immunity ◽

10.1128/iai.00539-10 ◽

2010 ◽

Vol 78 (10) ◽

pp. 4331-4340 ◽

Cited By ~ 29

Author(s):

William P. Weidanz ◽

GayeLyn LaFleur ◽

Andrew Brown ◽

James M. Burns ◽

Irene Gramaglia ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Nk Cells ◽

Nk Cell ◽

Γδ T Cells ◽

Cell Mediated Immunity ◽

Γδ T Cell ◽

Plasmodium Chabaudi ◽

Ifn Γ ◽

Time Courses

ABSTRACT Blood-stage Plasmodium chabaudi infections are suppressed by antibody-mediated immunity and/or cell-mediated immunity (CMI). To determine the contributions of NK cells and γδ T cells to protective immunity, C57BL/6 (wild-type [WT]) mice and B-cell-deficient (JH−/− ) mice were infected with P. chabaudi and depleted of NK cells or γδ T cells with monoclonal antibody. The time courses of parasitemia in NK-cell-depleted WT mice and JH−/− mice were similar to those of control mice, indicating that deficiencies in NK cells, NKT cells, or CD8+ T cells had little effect on parasitemia. In contrast, high levels of noncuring parasitemia occurred in JH−/− mice depleted of γδ T cells. Depletion of γδ T cells during chronic parasitemia in B-cell-deficient JH−/− mice resulted in an immediate and marked exacerbation of parasitemia, suggesting that γδ T cells have a direct killing effect in vivo on blood-stage parasites. Cytokine analyses revealed that levels of interleukin-10, gamma interferon (IFN-γ), and macrophage chemoattractant protein 1 (MCP-1) in the sera of γδ T-cell-depleted mice were significantly (P < 0.05) decreased compared to hamster immunoglobulin-injected controls, but these cytokine levels were similar in NK-cell-depleted mice and their controls. The time courses of parasitemia in CCR2−/− and JH−/− × CCR2−/− mice and in their controls were nearly identical, indicating that MCP-1 is not required for the control of parasitemia. Collectively, these data indicate that the suppression of acute P. chabaudi infection by CMI is γδ T cell dependent, is independent of NK cells, and may be attributed to the deficient IFN-γ response seen early in γδ T-cell-depleted mice.

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First-in-human dose escalation of ALPN-202, a conditional CD28 costimulator and dual checkpoint inhibitor, in advanced malignancies.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2547 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2547-2547

Author(s):

Justin C Moser ◽

Mark Voskoboynik ◽

Nehal J. Lakhani ◽

Michael Millward ◽

Diwakar Davar ◽

...

Keyword(s):

T Cell ◽

Colorectal Carcinoma ◽

Solid Tumors ◽

Dose Escalation ◽

Low Grade ◽

Checkpoint Inhibition ◽

Human Dose ◽

Cd28 Costimulation ◽

Advanced Malignancies ◽

Dose Levels

2547 Background: Strong preclinical rationale has emerged for combining checkpoint inhibition (CPI) with T cell costimulatory agonists, particularly CD28, a critical T cell costimulatory molecule recently recognized as a key target of checkpoint inhibition. ALPN-202 is a variant CD80 vIgD-Fc fusion that mediates PD-L1-dependent CD28 costimulation and inhibits the PD-L1 and CTLA-4 checkpoints. It has demonstrated superiority to CPI-only therapies in tumor models, while demonstrating favorable safety in preclinical toxicology studies. Methods: This is a cohort-based, open-label dose escalation and expansion study of ALPN-202 in adults with advanced solid tumors or lymphoma (NCT04186637). Subjects with cancers refractory to standard therapies (including approved CPIs), or cancers without available standard or curative therapy are eligible. After two planned single-subject cohorts, a standard 3+3 dose escalation has been implemented with two dose schedules in parallel, Q1W and Q3W. Objectives include evaluation of safety and tolerability, PK, PD and preliminary anticancer activity of ALPN-202. Disease assessments are evaluated by RECIST v1.1 for solid tumors or by Lugano Classification for lymphoma. Results: As of January 2021, 20 subjects with advanced malignancies have received ALPN-202. Dose-dependent PK and target saturation have been preliminarily observed. So far, ALPN-202 has been well tolerated at dose levels ranging from 0.001 to 1 mg/kg weekly, with no DLTs. Low-grade skin toxicities (grade 1-2 rash) have been observed in 4 subjects (20%). Among 11 evaluable subjects, an unconfirmed partial response has been observed in one subject with colorectal carcinoma, while stable disease has been observed in 5 subjects with colorectal carcinoma, mesothelioma (2), cholangiocarcinoma, and renal cell carcinoma -- for a preliminary clinical benefit (PR+SD) rate of 100% (4/4) at dose levels of 0.3 mg/kg and higher, or 54% (5/11) overall (table). The meeting presentation will update this data, which is expected to include the conclusion of Q1W dose escalation, as well as immune correlates. Conclusions: First-in-human dose escalation with ALPN-202 has been well tolerated at doses capable of engaging CD28 costimulation in vivo in association with dual PD-L1/CTLA-4 checkpoint inhibition, with early signs of anti-tumor activity. These findings suggest that CD28 agonism can be safely achieved in humans, and further suggest that dose expansion with ALPN-202 is warranted to assess the relevance of controlled CD28 costimulation as a novel approach to cancer immunotherapy. Clinical trial information: NCT04186637. [Table: see text]

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Immune-Mediated Adverse Events Associated with Ipilimumab CTLA-4 Blockade Therapy: The Underlying Mechanisms and Clinical Management

Scientifica ◽

10.1155/2013/857519 ◽

2013 ◽

Vol 2013 ◽

pp. 1-19 ◽

Cited By ~ 73

Author(s):

Ahmad Tarhini

Keyword(s):

T Cell ◽

Adverse Events ◽

T Cell Activation ◽

Cell Activation ◽

Treatment Guidelines ◽

Cell Mediated Immunity ◽

Low Grade ◽

Immune Mediated ◽

Organ Systems ◽

Treatment Naïve

Immunomodulation with the anti-CTLA-4 monoclonal antibody ipilimumab has been shown to extend overall survival (OS) in previously treated and treatment-naive patients with unresectable stage III or IV melanoma. Blockade of CTLA-4 signaling with ipilimumab prolongs T-cell activation and restores T-cell proliferation, thus amplifying T-cell-mediated immunity and the patient's capacity to mount an effective antitumor immune response. While this immunostimulation has unprecedented OS benefits in the melanoma setting, it can also result in immune-mediated effects on various organ systems, leading to immune-related adverse events (irAEs). Ipilimumab-associated irAEs are common and typically low grade and manageable, but can also be serious and life threatening. The skin and gastrointestinal tract are most frequently affected, while hepatic, endocrine, and neurologic events are less common. With proper management, most irAEs resolve within a relatively short time, with a predictable resolution pattern. Prompt and appropriate management of these irAEs is essential and treatment guidelines have been developed to assist oncologists and their teams. Implementation of these irAE management algorithms will help ensure that patients are able to benefit from ipilimumab therapy with adequate control of toxicities.

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Loss of Zfp335 triggers cGAS/STING-dependent apoptosis of post-β selection pre-T cells

10.1101/2021.12.03.471158 ◽

2021 ◽

Author(s):

Jeremy J Ratiu ◽

Qun Wang ◽

Naren Mehta ◽

Melissa J Harnois ◽

Devon DiPalma ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

Transcription Factor ◽

T Cell ◽

T Cell Development ◽

Cell Compartment ◽

Dependent Cell ◽

Selection For ◽

Sting Pathway ◽

And Control

AbstractProduction of a diverse peripheral T cell compartment requires massive expansion of the bone marrow progenitors that seed the thymus. There are two main phases of expansion during T cell development, following T lineage commitment at the DN2 stage and following successful rearrangement and selection for functional TCRβ chains in DN3 thymocytes, which promotes development of DN4 cells to the DP stage. Signals driving expansion of DN2 thymocytes are well studied, however, factors regulating the proliferation and survival of DN4 cells remain poorly understood. Here, we uncover an unexpected link between the transcription factor Zfp335 and control of cGAS/STING-dependent cell death in post-β-selection DN4 thymocytes. Zfp335 controls survival by sustaining expression of Ankle2, which suppresses cGAS/STING-dependent cell death. Together, this study identifies Zfp335 as a key transcription factor controlling the survival of proliferating post-β-selection thymocytes and demonstrates a key role for the cGAS/STING pathway driving apoptosis of developing T cells.

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Evaluation of T cell-mediated immunity in HIV-infected patients with helminthiasis

Infekcionnye bolezni ◽

10.20953/1729-9225-2021-1-33-38 ◽

2021 ◽

Vol 19 (1) ◽

pp. 33-38

Author(s):

R.O. Simonov ◽

◽

R.G. Yapparov ◽

D.A. Valishin ◽

E.M. Gareev ◽

...

Keyword(s):

T Cell ◽

Cell Count ◽

Control Group ◽

Cell Mediated Immunity ◽

Cd4 Cell Count ◽

Cd8 Cell ◽

Group 2 ◽

And Control ◽

Cd4 Cell ◽

Group 1

Objective. To analyze T cell-mediated immunity (subpopulations of CD3+, CD4+, and CD8+ lymphocytes) in HIV-infected patients with helminthiasis receiving or not receiving antiretroviral therapy (ART). Patients and methods. This study included 159 individuals; 100 of them had subclinical stage 3 HIV infection and helminthiasis (caused by different helminths) and were divided into two experimental groups depending on whether they received ART or not. The control group 1 comprised 29 HIV-positive people without helminthiasis not receiving ART, whereas the control group 2 included 30 HIV-negative people with helminthiasis. Patients in the experimental groups and control group 2 were followed up during the study and received anthelmintic treatment. The assessment of the immune status using monoclonal antibodies against specific antigens of subpopulations of T-lymphocytes (CD3+, CD4+ cells, cytotoxic T-cells-suppressors-CD8+ and CD4+/CD8+ ratio) was performed in the laboratory of the Republican Center for the Prevention and Control of AIDS and Infectious Diseases, Ufa, Russian Federation. Results. In this study, we evaluated the relative count of CD3+, CD4+, and CD8+ T cells in HIV-infected patients with helminthiasis at different time-pints during 6 months. We observed significant differences in the CD3+, CD3+CD4+, and CD3+CD8+ cell count between HIV-infected patients with helminthiasis on ART and without ART. Patients in the experimental group on ART demonstrated a significantly lower CD3+ cell count compared to patients in the experimental group not on ART (2.3 times lower; p < 0.01), as well as lower CD3+CD4+ cell count (1.5 times lower; p < 0.05) and CD4+CD8+ cell count (1.9 times lower; p < 0.05). Our findings suggest that HIV-infected people with helminthiasis on ART are more likely to have their CD3+, CD4+, and CD8+ Т-cell count normalized than those not receiving ART. Conclusion. The assessment of the immune status (T-cell medicated immunity) in the study groups demonstrated that HIVinfected patients with helminthiasis on ART presented with a gradual increase of the relative CD3+ cell count throughout the study (62.5 ± 5.6 %), whereas HIV-infected patients with helminthiasis receiving no ART presented with a gradual decrease of the relative CD3+ cell count (28.0 ± 4%). HIV-infected patients without helminthiasis and receiving no ART (control group 1) also demonstrated a decrease of the relative CD3+ cell count (28.1 ± 3.5%). We also observed a clear trend towards the normalization of relative CD3+CD4+ T-cell count (41.4 ± 8.2%) in HIV-infected patients with helminthiasis on ART, while patients from other groups (including HIV-infected patients with helminthiasis without ART and individuals in both control groups) demonstrated a tendency to a steady decline in the relative CD3+CD4+ cell count at all time-points. We also found that HIV-infected patients with helminthiasis on ART had their CD4+/CD8+ ratio back to almost normal by month 6 (45.7 ± 3.7%), whereas HIV-infected patients with helminthiasis without ART and patients from the control group 1 had their mean CD4+CD8+ ratio gradually decreasing throughout the study (27.5 ± 4.9% and 30.5 ± 7.1% respectively). The parameters of T-cell mediated immunity (subpopulations of CD3+, CD4+, and CD8+ lymphocytes) showed a more pronounced tendency to normalization in HIV-infected patients with helminthiasis who received ART. Our findings suggest that in HIV-infected patients with helminthiasis on ART, compensatory mechanisms of T-lymphocytes predominate, in contrast to HIV-infected patients with helminthiasis receiving no ART and the control group of HIV-infected patients receiving no ART, in whom we observed immunodeficiency of different grades. Key words: HIV infection, helminthiasis, T-cell immunity

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T-cell mediated immunity in murine malaria. I. Induction of T-cell dependent proliferative responses to Plasmodium chabaudi

Parasite Immunology ◽

10.1111/j.1365-3024.1984.tb00781.x ◽

1984 ◽

Vol 6 (1) ◽

pp. 51-62 ◽

Cited By ~ 5

Author(s):

A. K. CHEMTAI ◽

M. VAECK ◽

C. HAMERS-CASTERMAN ◽

R. HAMERS ◽

P. DE BAETSELIER

Keyword(s):

T Cell ◽

Cell Mediated Immunity ◽

Plasmodium Chabaudi

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Chronic Plasmodium chabaudi Infection Generates CD4 Memory T Cells with Increased T Cell Receptor Sensitivity but Poor Secondary Expansion and Increased Apoptosis

Infection and Immunity ◽

10.1128/iai.00744-16 ◽

2016 ◽

Vol 85 (3) ◽

Cited By ~ 4

Author(s):

Michael M. Opata ◽

Robin Stephens

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Receptor ◽

Chronic Infection ◽

Malaria Infection ◽

Memory T Cells ◽

Cell Receptor ◽

Blood Stage ◽

Effector Memory ◽

Plasmodium Chabaudi

ABSTRACT Exposure to blood-stage malaria infection is often persistent, leading to generation of CD4 effector and effector memory T cells that contribute to protection. We showed previously that chronic exposure to blood-stage Plasmodium chabaudi offers the best protection from parasitemia and pathology in reinfection cases, correlating with an increase in Th1 cells. Although much is known about the features of resting or exhausted memory T cells (Tmem), little is known about the functional capacities of chronically stimulated but protective T cells. To determine the functional capacity of CD4 T cells generated by chronic infection upon reexposure to parasite, we compared their responses to known features of classical Tmem. The numbers of cytokine-producing T cells increased following infection in the polyclonal populations, suggesting an increase in pathogen-specific T cells. Malaria antigen-specific B5 T cell receptor (TCR) transgenic (Tg) T cells from chronic infection proliferated on reinfection and were highly sensitive to TCR stimulation without costimulation, as shown for Tmem in acute stimulations. However, B5 Tmem did not accumulate more than naive B5 T cells in vivo or in vitro and became apoptotic. Failure to accumulate was partly the result of chronic stimulation, since eliminating persistent parasites before reinfection slightly increased the accumulation of B5 Tg T cells upon reinfection. The levels of specific gamma interferon-positive, interleukin-10-positive T cells, which protect animals from pathology, increased after malaria infection. These data demonstrate that although chronic infection generates a protective T cell population with increased TCR sensitivity and cytokine production, they do not reexpand upon reexposure due to increased apoptosis.

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