Toxoplasma gondii: CD8 T Cells Cry for CD4 Help

AbstractIn contrast to previous notions of the help-independency of memory CD8 T cells during secondary expansion, here we show that CD4 help is indispensable for the re-expansion of once-helped memory CD8 T cells, using a hematopoietic cell–specific dominant minor histocompatibility (H) antigen, H60, as a model antigen. H60-specific memory CD8 T cells generated during a helped primary response vigorously expanded only when rechallenged under helped conditions. The help requirement for an optimal secondary response was confirmed by a reduction in peak size by CD4 depletion, and was reproduced after skin transplantation. Helpless conditions or noncognate separate help during the secondary response resulted in a significant reduction in the peak size and different response kinetics. Providing CD4 help again during a tertiary challenge restored robust memory expansion; however, the repeated deprivation of help further reduced clonal expansion. Adoptively transferred memory CD8 T cells did not proliferate in CD40L−/− hosts. In the CD40−/− hosts, marginal memory expansion was detected after priming with male H60 cells but was completely abolished by priming with peptide-loaded CD40−/− cells, suggesting the essential role of CD40 and CD40L in memory responses. These results provide insight into the control of minor H antigen-specific CD8 T-cell responses, to maximize the graft-versus-leukemia response.

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Suppressive CD8+ T Cells Arise in the Absence of CD4 Help and Compromise Control of Persistent Virus

The Journal of Immunology ◽

10.4049/jimmunol.1003812 ◽

2011 ◽

Vol 186 (11) ◽

pp. 6218-6226 ◽

Cited By ~ 33

Author(s):

Michael J. Molloy ◽

Weijun Zhang ◽

Edward J. Usherwood

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Persistent Virus ◽

Cd4 Help

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Differential Regulation of Effector- and Central-Memory Responses to Toxoplasma gondii Infection by IL-12 Revealed by Tracking of Tgd057-Specific CD8+ T Cells

PLoS Pathogens ◽

10.1371/journal.ppat.1000815 ◽

2010 ◽

Vol 6 (3) ◽

pp. e1000815 ◽

Cited By ~ 70

Author(s):

Douglas C. Wilson ◽

Gijsbert M. Grotenbreg ◽

Kenian Liu ◽

Yanlin Zhao ◽

Eva-Maria Frickel ◽

...

Keyword(s):

T Cells ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Differential Regulation ◽

Central Memory ◽

Toxoplasma Gondii Infection

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Regulation of Microglia by CD4+ and CD8+ T Cells: Selective Analysis in CD45-congenic Normal and Toxoplasma gondii-infected Bone Marrow Chimeras

Brain Pathology ◽

10.1111/j.1750-3639.2001.tb00380.x ◽

2006 ◽

Vol 11 (1) ◽

pp. 44-55 ◽

Cited By ~ 18

Author(s):

Dirk Schlüter ◽

Timothy Meyer ◽

Andreas Strack ◽

Sabine Reiter ◽

Marianne Kretschmar ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Bone Marrow Chimeras ◽

Selective Analysis

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Host ER–parasitophorous vacuole interaction provides a route of entry for antigen cross-presentation in Toxoplasma gondii–infected dendritic cells

Journal of Experimental Medicine ◽

10.1084/jem.20082108 ◽

2009 ◽

Vol 206 (2) ◽

pp. 399-410 ◽

Cited By ~ 115

Author(s):

Romina S. Goldszmid ◽

Isabelle Coppens ◽

Avital Lev ◽

Pat Caspar ◽

Ira Mellman ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Toxoplasma Gondii ◽

Mhc Class I ◽

Cd8 T Cells ◽

Parasitophorous Vacuole ◽

Host Cells ◽

Class I ◽

Cross Presentation ◽

Infected Cells

Toxoplasma gondii tachyzoites infect host cells by an active invasion process leading to the formation of a specialized compartment, the parasitophorous vacuole (PV). PVs resist fusion with host cell endosomes and lysosomes and are thus distinct from phagosomes. Because the parasite remains sequestered within the PV, it is unclear how T. gondii–derived antigens (Ag’s) access the major histocompatibility complex (MHC) class I pathway for presentation to CD8+ T cells. We demonstrate that recruitment of host endoplasmic reticulum (hER) to the PV in T. gondii–infected dendritic cells (DCs) directly correlates with cross-priming of CD8+ T cells. Furthermore, we document by immunoelectron microscopy the transfer of hER components into the PV, a process indicative of direct fusion between the two compartments. In strong contrast, no association between hER and phagosomes or Ag presentation activity was observed in DCs containing phagocytosed live or dead parasites. Importantly, cross-presentation of parasite-derived Ag in actively infected cells was blocked when hER retrotranslocation was inhibited, indicating that the hER serves as a conduit for the transport of Ag between the PV and host cytosol. Collectively, these findings demonstrate that pathogen-driven hER–PV interaction can serve as an important mechanism for Ag entry into the MHC class I pathway and CD8+ T cell cross-priming.

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Peripheral self-reactivity regulates antigen-specific CD8 T-cell responses and cell division under physiological conditions

Open Biology ◽

10.1098/rsob.160293 ◽

2016 ◽

Vol 6 (11) ◽

pp. 160293 ◽

Cited By ~ 5

Author(s):

Lee Kim Swee ◽

Zhen Wei Tan ◽

Anna Sanecka ◽

Nagisa Yoshida ◽

Harshil Patel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Cd8 T Cell ◽

Effector Function ◽

Effector Functions ◽

Physiological Conditions ◽

Cell Clones

T-cell identity is established by the expression of a clonotypic T-cell receptor (TCR), generated by somatic rearrangement of TCRα and β genes. The properties of the TCR determine both the degree of self-reactivity and the repertoire of antigens that can be recognized. For CD8 T cells, the relationship between TCR identity—hence reactivity to self—and effector function(s) remains to be fully understood and has rarely been explored outside of the H-2 b haplotype. We measured the affinity of three structurally distinct CD8 T-cell-derived TCRs that recognize the identical H-2 L d -restricted epitope, derived from the Rop7 protein of Toxoplasma gondii . We used CD8 T cells obtained from mice generated by somatic cell nuclear transfer as the closest approximation of primary T cells with physiological TCR rearrangements and TCR expression levels. First, we demonstrate the common occurrence of secondary rearrangements in endogenously rearranged loci. Furthermore, we characterized and compared the response of Rop7-specific CD8 T-cell clones upon Toxoplasma gondii infection as well as effector function and TCR signalling upon antigenic stimulation in vitro . Antigen-independent TCR cross-linking in vitro uncovered profound intrinsic differences in the effector functions between T-cell clones. Finally, by assessing the degree of self-reactivity and comparing the transcriptomes of naive Rop7 CD8 T cells, we show that lower self-reactivity correlates with lower effector capacity, whereas higher self-reactivity is associated with enhanced effector function as well as cell cycle entry under physiological conditions. Altogether, our data show that potential effector functions and basal proliferation of CD8 T cells are set by self-reactivity thresholds.

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Direct CD4 Help Provision following Interaction of Memory CD4 and CD8 T Cells with Distinct Antigen-Presenting Dendritic Cells

The Journal of Immunology ◽

10.4049/jimmunol.0904209 ◽

2010 ◽

Vol 185 (2) ◽

pp. 1028-1036 ◽

Cited By ~ 13

Author(s):

Marie-Ghislaine de Goër de Herve ◽

Bamory Dembele ◽

Mélissa Vallée ◽

Florence Herr ◽

Anne Cariou ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Cd8 T Cells ◽

Cd4 Help ◽

Antigen Presenting

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Organ- and Disease-Stage-Specific Regulation of Toxoplasma gondii-Specific CD8-T-Cell Responses by CD4 T Cells

Infection and Immunity ◽

10.1128/iai.00098-06 ◽

2006 ◽

Vol 74 (10) ◽

pp. 5790-5801 ◽

Cited By ~ 26

Author(s):

Sonja Lütjen ◽

Sabine Soltek ◽

Simona Virna ◽

Martina Deckert ◽

Dirk Schlüter

Keyword(s):

T Cells ◽

T Cell ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Functional Activity ◽

Cd4 T Cells ◽

Cd8 T Cell ◽

Cd4 T Cell ◽

Ifn Γ

ABSTRACT Toxoplasma gondii induces a persistent central nervous system infection, which may be lethally reactivated in AIDS patients with low CD4 T-cell numbers. To analyze the role of CD4 T cells for the regulation of parasite-specific CD8 T cells, mice were infected with transgenic T. gondii expressing the CD8 T-cell antigen β-galactosidase (β-Gal). Depletion of CD4 T cells prior to infection did not affect frequencies of β-Gal876-884-specific (consisting of residues 876 to 884 of β-Gal) CD8 T cells but resulted in a pronounced reduction of intracerebral β-Gal-specific gamma interferon (IFN-γ)-producing and cytolytic CD8 T cells. After cessation of anti-CD4 treatment a normal T. gondii-specific CD4 T-cell response developed, but IFN-γ production of intracerebral β-Gal-specific CD8 T cells remained impaired. The important supportive role of CD4 T cells for the optimal functional activity of intracerebral CD8 T cells was also observed in mice that had been depleted of CD4 T cells during chronic toxoplasmosis. Reinfection of chronically infected mice that had been depleted of CD4 T cells during either the acute or chronic stage of infection resulted in an enhanced proliferation of β-Gal-specific IFN-γ-producing splenic CD8 T cells. However, reinfection of chronically infected mice that had been depleted of CD4 T cells in the acute stage of infection did not reverse the impaired IFN-γ production of intracerebral CD8 T cells. Collectively, these findings illustrate that CD4 T cells are not required for the induction and maintenance of parasite-specific CD8 T cells but, depending on the stage of infection, the infected organ and parasite challenge infection regulate the functional activity of intracerebral CD8 T cells.

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Early Th2 cytokine production in Heligmosomoides polygyrus and Toxoplasma gondii co-infected mice is associated with reduced IFNγ production, increased parasite loads and increased mortality

10.1101/2021.05.27.445631 ◽

2021 ◽

Author(s):

Edina K. Szabo ◽

Christina Bowhay ◽

Namratha Badawadagi ◽

Beatrice Fung ◽

Camila Gaio ◽

...

Keyword(s):

T Cells ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Γδ T Cells ◽

Protozoan Parasite ◽

Careful Consideration ◽

Single Infection ◽

Mesenteric Lymph Nodes ◽

Heligmosomoides Polygyrus ◽

Infection Dynamics

Co-infections are a common reality but understanding how the immune system responds in this context is complex and can be unpredictable. Despite this, it is key to develop models that will provide better translatability to real world situations. Heligmosomoides polygyrus (parasitic roundworm) and Toxoplasma gondii (protozoan parasite) are well studied organisms that stimulate a characteristic Th2 and Th1 response respectively. IFNγ-producing T cells, NK and γδ T cells contribute to early protective immunity during T. gondii infection. To minimise immunopathology, IL-10 is also key to a successful response. Previous research has found H. polygyrus to improve survival during co-infection with both parasites. IFNγ-producing CD4+ and CD8+ T cells were implicated in this protection. Using a similar approach, we have found the opposite. Our co-infected animals displayed greater mortality and intestinal pathology than either single infection. This was associated with an early increase in Th2 cytokines in the Peyers patches, mesenteric lymph nodes and spleen. Co-infected animals also had reduced IFNγ producing cells at day 5 post T. gondii infection in the Peyers patches (CD8 T cells only) and in the MLN (NK, NKT, γδ T, CD4+ T and CD8+ T cells). This correlated with increased parasite loads in the MLN at 10 days post T. gondii infection. Our results demonstrate that co-infection dynamics can vary dramatically and that careful consideration needs to be taken when interpreting data in each situation.

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