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

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      JCI Insight
      American Society for Clinical Investigation

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          Abstract

          <p class="first" id="d9125542e204">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 <sup>+</sup> and CD8 <sup>+</sup> 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 CD8 <sup>dim</sup> T cells with an innate-like profile (Granzyme B <sup>hi</sup>, IFNγ <sup>low</sup>, TNFα <sup>low</sup>, PLFZ <sup>hi</sup>, ID2 <sup>hi</sup>, IKZF2 <sup>hi</sup>) in contrast to age-matched children residing in a low pathogen–exposure area who display a more conventional CD8 <sup>bright</sup> profile (IFNγ <sup>+</sup>, TNFα <sup>+</sup>, CCL4 <sup>+</sup>). 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 CD8 <sup>dim</sup> T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses. </p><p class="first" id="d9125542e251">Children repetitively exposed to high parasite burden develop a population of uncoventional CD8+ T cells with innate-like transcriptional features and function. </p>

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          Memory T cell subsets, migration patterns, and tissue residence.

          Tissues such as the skin and mucosae are frequently exposed to microbial pathogens. Infectious agents must be quickly and efficiently controlled by our immune system, but the low frequency of naive T cells specific for any one pathogen means dependence on primary responses initiated in draining lymph nodes, often allowing time for serious infection to develop. These responses imprint effectors with the capacity to home to infected tissues; this process, combined with inflammatory signals, ensures the effective targeting of primary immunity. Upon vaccination or previous pathogen exposure, increased pathogen-specific T cell numbers together with altered migratory patterns of memory T cells can greatly improve immune efficacy, ensuring infections are prevented or at least remain subclinical. Until recently, memory T cell populations were considered to comprise central memory T cells (TCM), which are restricted to the secondary lymphoid tissues and blood, and effector memory T cells (TEM), which broadly migrate between peripheral tissues, the blood, and the spleen. Here we review evidence for these two memory populations, highlight a relatively new player, the tissue-resident memory T cell (TRM), and emphasize the potential differences between the migratory patterns of CD4(+) and CD8(+) T cells. This new understanding raises important considerations for vaccine design and for the measurement of immune parameters critical to the control of infectious disease, autoimmunity, and cancer.
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            The silent threat: asymptomatic parasitemia and malaria transmission.

            Scale-up of malaria control interventions has resulted in a substantial decline in global malaria morbidity and mortality. Despite this achievement, there is evidence that current interventions alone will not lead to malaria elimination in most malaria-endemic areas and additional strategies need to be considered. Use of antimalarial drugs to target the reservoir of malaria infection is an option to reduce the transmission of malaria between humans and mosquito vectors. However, a large proportion of human malaria infections are asymptomatic, requiring treatment that is not triggered by care-seeking for clinical illness. This article reviews the evidence that asymptomatic malaria infection plays an important role in malaria transmission and that interventions to target this parasite reservoir may be needed to achieve malaria elimination in both low- and high-transmission areas.
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              The heterogeneity of human CD127(+) innate lymphoid cells revealed by single-cell RNA sequencing.

              Innate lymphoid cells (ILCs) are increasingly appreciated as important participants in homeostasis and inflammation. Substantial plasticity and heterogeneity among ILC populations have been reported. Here we have delineated the heterogeneity of human ILCs through single-cell RNA sequencing of several hundreds of individual tonsil CD127(+) ILCs and natural killer (NK) cells. Unbiased transcriptional clustering revealed four distinct populations, corresponding to ILC1 cells, ILC2 cells, ILC3 cells and NK cells, with their respective transcriptomes recapitulating known as well as unknown transcriptional profiles. The single-cell resolution additionally divulged three transcriptionally and functionally diverse subpopulations of ILC3 cells. Our systematic comparison of single-cell transcriptional variation within and between ILC populations provides new insight into ILC biology during homeostasis, with additional implications for dysregulation of the immune system.
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                Author and article information

                Journal
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                August 3 2017
                August 3 2017
                August 3 2017
                August 3 2017
                August 3 2017
                August 3 2017
                August 3 2017
                August 3 2017
                : 2
                : 15
                Article
                10.1172/jci.insight.93814
                5543908
                28768916
                477e28e4-60c8-4840-b11e-8ca22e51ce01
                © 2017
                History

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