The Mechanism and Significance of Deletion of Parasite-specific CD4<b><sup>+</sup></b>T Cells in Malaria Infection

Xu, Huji; Wipasa, Jiraprapa; Yan, Huaru; Zeng, Ming; Makobongo, Morris O.; Finkelman, Fred D.; Kelso, Anne; Good, Michael F.

doi:10.1084/jem.20011174

Cited by 142 publications

(136 citation statements)

References 58 publications

Supporting

Mentioning

123

Contrasting

Unclassified

Order By: Relevance

“…Minor differences in HGXPRT may alter the T cell response to the protein. It is also worth noting that parasite infection is known to lead to apoptosis of human mononuclear cells (30) and of parasite-specific CD4 ϩ T cells in vivo in rodent systems (31,32). A further possibility is that HGXPRT liberated from pRBC cytoplasm into the plasma at the time of pRBC rupture may tolerize the immune system (33).…”

Section: Discussionmentioning

confidence: 99%

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

Makobongo

Riding

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Although there is good evidence that immunity to the blood stages of malaria parasites can be mediated by different effector components of the adaptive immune system, target antigens for a principal component, effector CD4 ؉ T cells, have never been defined. We generated CD4 ؉ T cell lines to fractions of native antigens from the blood stages of the rodent parasite, Plasmodium yoelii, and identified fraction-specific T cells that had a Th1 phenotype (producing IL-2, IFN-␥, and tumor necrosis factor-␣, but not IL-4, after antigenic stimulation). These T cells could inhibit parasite growth in recipient severe combined immunodeficient mice. Nterminal sequencing of the fraction showed identity with hypoxanthine guanine xanthine phosphoribosyl transferase (HGXPRT). Recombinant HGXPRT from the human malaria parasite, Plasmodium falciparum, activated the T cells in vitro, and immunization of normal mice with recombinant HGXPRT reduced parasite growth rates in all mice after challenge.A lthough it is known that immunity to malaria can be mediated by different immune mechanisms (1-4), to date only target antigens for antibodies have been defined, and these targets are either variant or demonstrate allelic polymorphism (5). CD4 ϩ T cells can adoptively transfer resistance to malaria (3, 6, 7) in rodent models, but target antigens have not been defined. Of interest, CD4 ϩ T cells displaying a Th1 cytokine profile (IL-2-and IFN-␥-secreting) and specific for the major merozoite surface protein 1 (MSP1 19 ) of Plasmodium yoelii (a leading vaccine candidate homologue) are unable to transfer resistance, and immunization of mice with defined T cell epitopes from MSP1 19 did not render the mice resistant (8). Identification of a target antigen(s) would provide an additional vaccine strategy for vaccine design. The goal of this study was to define such target antigens in the rodent model, P. yoelii. Materials and MethodsMice. Four-to 6-week-old normal BALB͞c, athymic BALB͞c nude, and BALB͞c severe combined immunodeficient (SCID) mice were used when 6-8 weeks old.Parasites and Parasitemia. P. yoelii 17XNL was maintained by passaging between infected and uninfected mice via the i.p. route. A thin blood smear was air-dried and stained using Diff-Quick (Lab Aids, Narrabeen, Australia).Preparation of Parasite Antigens. Preparation of whole parasite antigen (pRBC). Parasitized red blood cells (pRBC) in PBS were lysed by incubation in erythrocyte lysis buffer (0.17 M Tris-hydroxymethyl aminomethane͞0.16 M ammonium chloride; pH 7.2) at 37°C for 10 min. The parasites were then freeze-thawed at least three times, sonicated at 4°C to break up the parasites, aliquoted, and stored at Ϫ70°C to be used for in vitro cell cultures. Preparation of soluble parasite antigen (sAg).RBCs were lysed by incubation of the blood in 0.01% saponin͞PBS at 37°C for 20 min in the presence of protease inhibitors (Sigma). The blood was then given another wash in saponin͞PBS buffer before the pRBCs were sonicated in cold PBS at 4°C.After sonication, the lysate was ...

show abstract

Section: Discussionmentioning

confidence: 99%

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

Makobongo

Riding

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…In a follow-up study using antibiotic pretreated mice, the authors showed that decreased IFN-␥ production during early inflammation was correlated with an absence of the contraction phase of the primary CD8 ϩ response (5). Furthermore, using parasite-specific CD4 ϩ T cell lines another report showed that IFN-␥ indeed is involved in the depletion of effector cells during infections (31).…”

Section: Discussionmentioning

confidence: 99%

Self-Limitation of Th1-Mediated Inflammation by IFN-γ

Feuerer

Eulenburg

Loddenkemper

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

IFN-γ is an effector cytokine of cell-mediated immunity that plays an essential role in both innate and adaptive phases of an immune response. Interestingly, in several Th1-dependent autoimmune models, lack of IFN-γ is associated with an acceleration of disease. To distinguish the influence of IFN-γ on the polarization of naive precursors from the influence on effector cells, we used an adoptive transfer model of differentiated Ag-specific Th1 cells. In this study, IFN-γ displayed a dual function in a Th1-dependent immune reaction. In the early phase, IFN-γ accelerated the inflammation, whereas in the late phase it mediated the process of self-limitation. We demonstrated that IFN-γ limits the number of Th1 effector cells after Ag challenge. Studies using IFN-γR−/− mice as recipients showed that IFN-γ acts indirectly via host cells to regulate the pool size of Th1 cells. NO was a downstream effector molecule. Transfer experiments of Th1 cells into IFN-γ−/− mice revealed that Th1 cells control both themselves and the corresponding inflammation by the release of IFN-γ. Thus, the proinflammatory cytokine IFN-γ can act as a negative feedback regulator to control Th1-mediated immune responses.

show abstract

“…In addition, ~99% of parasite‐specific CD4 + T cells were lost after P. chaubadi infection 119. Another study showed that the loss of immune cells during malaria infection is unique to parasite‐specific CD4 + T cells, as ovalbumin‐specific T cells were not depleted in a murine malaria model 120. Similarly, in humans, the absolute numbers of T cells markedly increased after treatment as opposed to levels observed during concurrent infection, suggesting malaria‐induced lymphopenia 121, 122, 123, 124.…”

Section: Mechanisms Of Reduced Inflammation At High Exposure Levelsmentioning

confidence: 99%

Evaluating antidisease immunity to malaria and implications for vaccine design

Ademolue

Awandare

2017

Immunology

View full text Add to dashboard Cite

SummaryImmunity to malaria could be categorized broadly as antiparasite or antidisease immunity. While most vaccine research efforts have focused on antiparasite immunity, the evidence from endemic populations suggest that antidisease immunity is an important component of natural immunity to malaria. The processes that mediate antidisease immunity have, however, attracted little to no attention, and most interests have been directed towards the antibody responses. This review evaluates the evidence for antidisease immunity in endemic areas and discusses the possible mechanisms responsible for it. Given the key role that inflammation plays in the pathogenesis of malaria, regulation of the inflammatory response appears to be a major mechanism for antidisease immunity in naturally exposed individuals.

show abstract

The Mechanism and Significance of Deletion of Parasite-specific CD4⁺T Cells in Malaria Infection

Cited by 142 publications

References 58 publications

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

Self-Limitation of Th1-Mediated Inflammation by IFN-γ

Evaluating antidisease immunity to malaria and implications for vaccine design

Contact Info

Product

Resources

About

The Mechanism and Significance of Deletion of Parasite-specific CD4+T Cells in Malaria Infection

Cited by 142 publications

References 58 publications

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

The purine salvage enzyme hypoxanthine guanine xanthine phosphoribosyl transferase is a major target antigen for cell-mediated immunity to malaria

Self-Limitation of Th1-Mediated Inflammation by IFN-γ

Evaluating antidisease immunity to malaria and implications for vaccine design

Contact Info

Product

Resources

About

The Mechanism and Significance of Deletion of Parasite-specific CD4⁺T Cells in Malaria Infection