Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation

Ryg-Cornejo, Victoria; Ioannidis, Lisa J; Ly, Ann; Chiu, Chris; Tellier, Julie; Hill, Danika L.; Preston, Simon; Pellegrini, Marc; Yu, Di; Nutt, Stephen L.; Kallies, Axel; Hansen, Diana S.

doi:10.1016/j.celrep.2015.12.006

Cited by 206 publications

(252 citation statements)

References 49 publications

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“…These would be interesting targets to explore in this system as well. Indeed, extended expression of type I IFN or IFN-␥ has recently been shown to inhibit germinal center production in chronic P. berghei and P. yoelii infections (40,41).…”

Section: Discussionmentioning

confidence: 99%

“…Actually, CD4 T cell exhaustion has not been well documented in any situation. Instead, there is a concerted change in the cytokine profile of chronically stimulated T cells in LCMV and malaria away from Th1 or Tfh commitment (40,41,(47)(48)(49), suggesting that the effect of chronic infection on CD4 T cells is different than that on CD8 cells. On the other hand, PD-1 is expressed on human T cells in P. falciparum infections (44), and T cell proliferation is reduced in areas of continuous exposure to P. falciparum compared to those with successful control programs (21).…”

Section: Discussionmentioning

confidence: 99%

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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

Opata

Stephens

2017

Infect Immun

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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. KEYWORDS T cells, immune memory, malaria, mouse Blood-stage malaria infection, like other chronic infections, generates effector memory T cells (Tem) in mice and humans (1, 2). Children living in areas with high malaria transmission demonstrate a decrease in the incidence of malaria disease as they grow older (3). This decrease in malarial incidence is associated with an increased number of gamma interferon (IFN-␥)-producing effector/effector memory CD4 T cells upon parasite exposure (1, 2). However, the levels of malaria-responsive T cells and malaria antigen-specific antibody titers decay over time (4-6), as does clinical immunity. These data support the conclusion that there are disease-protective memory B and T cells in individuals repeatedly infected with malaria that decay in the absence of exposure. However, the effector mechanisms by which these immune cells contribute to protection from repeated parasitemia and malaria disease are poorly understood.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

Opata

Stephens

2017

Infect Immun

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“…We have now extended those observations by providing evidence that a lack of CXCL10 during infection results in significantly increased numbers of CXCR3 + CD4 + Tfh cells in the spleen. We have recently found that P. berghei ANKA infection induces primarily a population of Tfh cell precursors, which, despite normal Bcl-6 and IL-21 expression, display low levels of PD-1 and CXCR5 and coexpress Th1-associated molecules such as T-bet and CXCR3 (31). Although these cells do not appear to efficiently support GC responses, work by others (45) suggested that they are required to provide help for the induction of extrafollicular Ab responses.…”

Section: Discussionmentioning

confidence: 99%

Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease

Ioannidis

Nie

et al. 2016

The Journal of Immunology

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CXCL10, or IFN-γ–inducible protein 10, is a biomarker associated with increased risk for Plasmodium falciparum–mediated cerebral malaria (CM). Consistent with this, we have previously shown that CXCL10 neutralization or genetic deletion alleviates brain intravascular inflammation and protects Plasmodium berghei ANKA-infected mice from CM. In addition to organ-specific effects, the absence of CXCL10 during infection was also found to reduce parasite biomass. To identify the cellular sources of CXCL10 responsible for these processes, we irradiated and reconstituted wild-type (WT) and CXCL10−/− mice with bone marrow from either WT or CXCL10−/− mice. Similar to CXCL10−/− mice, chimeras unable to express CXCL10 in hematopoietic-derived cells controlled infection more efficiently than WT controls. In contrast, expression of CXCL10 in knockout mice reconstituted with WT bone marrow resulted in high parasite biomass levels, higher brain parasite and leukocyte sequestration rates, and increased susceptibility to CM. Neutrophils and inflammatory monocytes were identified as the main cellular sources of CXCL10 responsible for the induction of these processes. The improved control of parasitemia observed in the absence of CXCL10-mediated trafficking was associated with a preferential accumulation of CXCR3+CD4+ T follicular helper cells in the spleen and enhanced Ab responses to infection. These results are consistent with the notion that some inflammatory responses elicited in response to malaria infection contribute to the development of high parasite densities involved in the induction of severe disease in target organs.

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“…CPS-CQimmunized individuals reacted preferentially to 84 preerythrocytic Ags, while the Kenyan participants reacted preferentially to 238 blood-stage Ags. Both groups reacted to about 90 cross-stage Ags (53,54). It is possible that different antigenic profiles contribute to the differences in immune sustainability or/and the CQ drug may modify the T and B cell memory responses.…”

Section: Malaria Vaccinesmentioning

confidence: 99%

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

Plotkin

Edwards

et al. 2017

Clin Vaccine Immunol

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Since the middle of the 20th century, vaccines have made a significant public health impact by controlling infectious diseases globally. Although long-term protection has been achieved with some vaccines, immunity wanes over time with others, resulting in outbreaks or epidemics of infectious diseases. Long-term protection against infectious agents that have a complex life cycle and antigenic variation remains a key challenge. Novel strategies to characterize the short-and long-term immune responses to vaccines and to induce immune responses that mimic natural infection have recently emerged. New technologies and approaches in vaccinology, such as adjuvants, delivery systems, and antigen formulations, have the potential to elicit more durable protection and fewer adverse reactions; together with in vitro systems, these technologies have the capacity to model and accelerate vaccine development. The National Institute of Allergy and Infectious Diseases (NIAID) held a workshop on 19 September 2016 that focused on waning immunity to selected vaccines (for Bordetella pertussis, Salmonella enterica serovar Typhi, Neisseria meningitidis, influenza, mumps, and malaria), with an emphasis on identifying knowledge gaps, future research needs, and how this information can inform development of more effective vaccines for infectious diseases.

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Severe Malaria Infections Impair Germinal Center Responses by Inhibiting T Follicular Helper Cell Differentiation

Cited by 206 publications

References 49 publications

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

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

Monocyte- and Neutrophil-Derived CXCL10 Impairs Efficient Control of Blood-Stage Malaria Infection and Promotes Severe Disease

Waning Immunity and Microbial Vaccines—Workshop of the National Institute of Allergy and Infectious Diseases

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