Circulating Th1-Cell-type Tfh Cells that Exhibit Impaired B Cell Help Are Preferentially Activated during Acute Malaria in Children

Obeng-Adjei, Nyamekye; Portugal, Sílvia; Tran, Tuan M.; Yazew, Takele; Skinner, Jeff; Li, Shanping; Jain, Aarti; Felgner, Philip L.; Doumbo, Ogobara K.; Kayentao, Kassoum; Ongoïba, Aïssata; Traoré, Boubacar; Crompton, Peter D.

doi:10.1016/j.celrep.2015.09.004

Cited by 205 publications

(295 citation statements)

References 47 publications

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“…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: 94%

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: 94%

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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“…For example, many studies have demonstrated that T H 1 cells maintain flexibility with the T FH cell type (19, 30, 48). More recently, there have also been reports of T H 1-biased T FH cell populations (49, 50). Corroborating these studies, our laboratory has previously demonstrated that T H 1 cells are capable of upregulating a Bcl-6-dependent T FH -like cell state in response to altered IL-2 signaling (28, 30).…”

Section: Resultsmentioning

confidence: 99%

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells

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Powell

Baker

et al. 2017

The Journal of Immunology

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Bcl-6 (B cell lymphoma-6) is a transcriptional repressor required for the differentiation of T follicular helper (TFH) cell populations. Currently, the molecular mechanisms underlying the transcriptional regulation of Bcl-6 expression are unclear. Here, we have identified the Ikaros zinc finger (IkZF) transcription factors Aiolos and Ikaros as novel regulators of Bcl-6. We found that increased expression of Bcl-6 in CD4+ T helper cell populations correlated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Furthermore, overexpression of Aiolos or Ikaros, but not the related family member Eos, was sufficient to induce Bcl6 promoter activity. Intriguingly, STAT3, a known Bcl-6 transcriptional regulator, physically interacted with Aiolos to form a transcription factor complex capable of inducing the expression of Bcl6 and the TFH-associated cytokine receptor Il6ra. Importantly, in vivo studies revealed that the expression of Aiolos was elevated in antigen-specific TFH cells compared to that observed in non-TFH effector T helper cells generated in response to influenza infection. Collectively, these data describe a novel regulatory mechanism wherein STAT3 and the IkZF transcription factors Aiolos and Ikaros cooperate to regulate Bcl-6 expression.

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“…These observations suggest the involvement of ICOS + PD-1 + CXCR3 + cTfh cells in Ab responses, likely before they migrate out to the circulation. These observations were unexpected and perplexing, as multiple studies including ours demonstrated that CXCR3 + subset among cTfh cells was poor at providing help to B cells789. Furthermore, it is possible that the emergence of ICOS + PD-1 + CXCR3 + cTfh cells reflects only a fraction of Tfh responses induced by TIV, and that other Tfh cells which remain in the lymph nodes are the major helpers directly associated with the Ab response.…”

mentioning

confidence: 82%

ICOS+PD-1+CXCR3+ T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination

Bentebibel

Khurana

Schmitt

et al. 2016

Sci Rep

139

141

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The immune mechanism leading to the generation of protective antibody responses following influenza trivalent inactivated vaccine (TIV) vaccinations remains largely uncharacterized. We recently reported that TIV vaccination induced a transient increase of circulating ICOS+PD-1+CXCR3+ T follicular helper (cTfh) cells in blood, which positively correlated with the induction of protective antibody responses measured at day 28. However, whether and how these T cells directly contribute to antibody response remains unclear. In this study, we analyzed the changes after TIV vaccination in the amount and the avidity of the polyclonal antibodies specific for the HA1 subunit of the pandemic H1N1 virus, and analyzed the correlation with the increase of ICOS+PD-1+CXCR3+ cTfh cells. We found that both the amount and the avidity of specific antibodies rapidly increased during the first 7 days after TIV. Importantly, the increase of ICOS+PD-1+CXCR3+ cTfh cells strongly correlated with the increase in the avidity of antibodies, particularly in subjects who did not have high affinity antibodies at baseline. We propose that ICOS+PD-1+CXCR3+ Tfh cells directly contribute to the generation of high-avidity antibodies after TIV vaccinations by selectively interacting with high affinity B cells at extrafollicular sites.

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Circulating Th1-Cell-type Tfh Cells that Exhibit Impaired B Cell Help Are Preferentially Activated during Acute Malaria in Children

Cited by 205 publications

References 47 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

Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells

ICOS+PD-1+CXCR3+ T follicular helper cells contribute to the generation of high-avidity antibodies following influenza vaccination

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