Loss and dysfunction of Vδ2
            <sup>+</sup>
            γδ T cells are associated with clinical tolerance to malaria

Jagannathan, Prasanna; Kim, Charles C.; Greenhouse, Bryan; Nankya, Felistas; Bowen, Katherine; Eccles-James, Ijeoma; Muhindo, Mary; Arinaitwe, Emmanuel; Tappero, Jordan W.; Kamya, Moses R.; Dorsey, Grant; Feeney, Margaret E.

doi:10.1126/scitranslmed.3009793

Cited by 117 publications

(180 citation statements)

References 48 publications

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“…+ cells, a subset of γδ T lymphocytes that does not require antigen processing to induce T cell receptor-mediated (TCR-mediated) cytolytic death of infected red blood cells via granulysin (9)(10)(11)(12)(13). These findings support the premise that persistent malaria infection induces immunological adaptation in humans, favoring a less inflammatory environment.…”

Section: Vδ2supporting

confidence: 74%

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Falanga¹,

Frascoli²,

Kaymaz³

et al. 2017

JCI Insight

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Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4+ and CD8+ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8dim T cells with an innate-like profile (Granzyme Bhi, IFNγlow, TNFαlow, PLFZhi, ID2hi, IKZF2hi) in contrast to age-matched children residing in a low pathogen-exposure area who display a more conventional CD8bright profile (IFNγ+, TNFα+, CCL4+). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses

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Section: Vδ2supporting

confidence: 74%

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Falanga¹,

Frascoli²,

Kaymaz³

et al. 2017

JCI Insight

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“…Interestingly, two populations of γδ T cells were visible that had varying expression levels of the γδ TCR (Fig 1a, top panel). The γδTCR lo population was enriched for CD45RO expression, suggesting that these might represent the Vδ2 subset (27, 28). Therefore, we enumerated the Vδ2 subset after last vaccine dose and assessed the relationship to protection.…”

Section: Resultsmentioning

confidence: 99%

“…These data supported the findings from the ex vivo assays that Vδ2 T cells were associated with protection. Other genes in the top 15 included those associated with regulation of proliferative responses (TGM2, SIPR5), a marker of plasma cells and activated γδ T cells (SLAMF7) (27) and activating receptor for NK cells (NCR1).…”

Section: Resultsmentioning

confidence: 99%

γδ T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations

Zaidi

Diallo²,

Conteh

et al. 2017

The Journal of Immunology

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Whole sporozoite vaccines confer sterilizing immunity to malaria-naïve individuals by unknown mechanisms. In the first-ever PfSPZ Vaccine trial in a malaria endemic population, Vδ2 γδT cells were significantly elevated, and Vγ9/Vδ2 transcripts ranked as most-upregulated, in vaccinees that were protected from P. falciparum infection. In a mouse model, absence of γδ T cells during vaccination impaired protective CD8 T cell responses, and ablated sterile protection. γδ T cells were not required for CSP-specific antibody responses, and γδ T cell depletion before infectious challenge did not ablate protection. γδ T cells alone were insufficient to induce protection and required the presence of CD8α+ dendritic cells. In the absence of γδ T cells, CD8α+ DC did not accumulate in the livers of vaccinated mice. Altogether our results show that γδ T cells were essential for the induction of sterile immunity during whole organism vaccination.

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“…Repeated malaria exposure can lead to attenuation of the cell-mediated proinflammatory responses through either dysfunction and/or exhaustion of immune cell subsets that produce proinflammatory mediators (e.g., Vd2 + gd T cells [99]) or the expansion of immunoregulatory cells that control inflammation (e.g., P. falciparum-specific CD4 + Foxp3 À T cells [100]). It has also been suggested that, similar to endotoxin tolerance, regulation of the Toll-like receptor (TLR) signaling pathway, which recognizes highly conserved PAMPs, could also induce refractoriness of immune cells to produce inflammatory cytokines after repeated malaria stimulations [33].…”

Section: Cellular Downregulation Of P Falciparum-inducible Inflammationmentioning

confidence: 99%

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Galatas

Bassat

Mayor

2016

Trends in Parasitology

119

122

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With malaria elimination back on the international agenda, programs face the challenge of targeting all Plasmodium infections, not only symptomatic cases. As asymptomatic individuals are unlikely to seek treatment, they are missed by passive surveillance while remaining infectious to mosquitoes, thus acting as silent reservoirs of transmission. To estimate the risk of asymptomatic infections in various phases of malaria elimination, we need a deeper understanding of the underlying mechanisms favoring carriage over disease, which may involve both pathogen and host factors. Here we review our current knowledge on the determinants leading to Plasmodium falciparum symptomless infections. Understanding the host-pathogen interactions that are most likely to affect transitions between malaria disease states could guide the development of tools to tackle asymptomatic carriers in elimination settings. Being AsymptomaticPeaceful coexistence with the infected host, rarely causing clinical symptoms, is a common but poorly understood phenomenon that occurs for many human pathogens [1]. Because such asymptomatic cases of infection occur without eventual overt symptoms, they do not come to clinical attention, thus representing a large hidden reservoir of active infection that permits their persistence and eventual spread to other human hosts. This is the case for many malaria infections in semi-immune individuals from endemic areas, which commonly cause a mild febrile illness or no apparent symptoms at all, while keeping parasite numbers at low densities [2] (Box 1).Carriage of asymptomatic malaria (see Glossary) infections, being at the same time difficult to detect and to manage, has considerable implications for the design and use of malaria elimination strategies. Symptomless infections that persist during the dry season in areas of seasonal transmission have been suggested to seed the malaria outbreaks after annual rains when mosquitoes reappear [3]. Similarly, asymptomatic parasitemia may potentially contribute to persistence of transmission in low-transmission settings [4]. However, the precise contribution of asymptomatic malaria to transmission in areas that have achieved substantial reductions in the malaria burden remains a matter of debate [5], as is the assumption that detecting and targeting these individuals for radical treatment, as opposed to using mass drug administration approaches, would be an efficient and effective tactic. Moreover, eradication in Europe, North America, and other parts of the world using no better diagnostics than microscopy [6] suggest that key determinants of success might not be finding the last parasite. From a practical point of view, the proportion of asymptomatic infections in certain situations and phases of malaria elimination may impose the need for modifications of detection methods (active versus passive case detection) [7] if, for example, symptom-based surveillance at health facilities is insufficient and mass blood surveys are necessary to inform the design of elimination i...

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Loss and dysfunction of Vδ2 ⁺ γδ T cells are associated with clinical tolerance to malaria

Cited by 117 publications

References 48 publications

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

γδ T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

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Loss and dysfunction of Vδ2 + γδ T cells are associated with clinical tolerance to malaria

Cited by 117 publications

References 48 publications

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

γδ T Cells Are Required for the Induction of Sterile Immunity during Irradiated Sporozoite Vaccinations

Malaria Parasites in the Asymptomatic: Looking for the Hay in the Haystack

Contact Info

Product

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Loss and dysfunction of Vδ2 ⁺ γδ T cells are associated with clinical tolerance to malaria