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Transcriptional Memory-Like Imprints and Enhanced Functional Activity in ?? T Cells Following Resolution of Malaria Infection.

ABSTRACT: ?? T cells play an essential role in the immune response to many pathogens, including Plasmodium. However, long-lasting effects of infection on the ?? T cell population still remain inadequately understood. This study focused on assessing molecular and functional changes that persist in the ?? T cell population following resolution of malaria infection. We investigated transcriptional changes and memory-like functional capacity of malaria pre-exposed ?? T cells using a Plasmodium chabaudi infection model. We show that multiple genes associated with effector function (chemokines, cytokines and cytotoxicity) and antigen-presentation were upregulated in P. chabaudi-exposed ?? T cells compared to ?? T cells from naïve mice. This transcriptional profile was positively correlated with profiles observed in conventional memory CD8+ T cells and was accompanied by enhanced reactivation upon secondary encounter with Plasmodium-infected red blood cells in vitro. Collectively our data demonstrate that Plasmodium exposure result in "memory-like imprints" in the ?? T cell population and also promotes ?? T cells that can support antigen-presentation during subsequent infections.

SUBMITTER: Kumarasingha R

PROVIDER: S-EPMC7591758 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Publications

Transcriptional Memory-Like Imprints and Enhanced Functional Activity in γδ T Cells Following Resolution of Malaria Infection.

Kumarasingha Rasika R Ioannidis Lisa J LJ Abeysekera Waruni W Studniberg Stephanie S Wijesurendra Dinidu D Mazhari Ramin R Poole Daniel P DP Mueller Ivo I Schofield Louis L Hansen Diana S DS Eriksson Emily M EM

Frontiers in immunology 20201014

γδ T cells play an essential role in the immune response to many pathogens, including <i>Plasmodium</i>. However, long-lasting effects of infection on the γδ T cell population still remain inadequately understood. This study focused on assessing molecular and functional changes that persist in the γδ T cell population following resolution of malaria infection. We investigated transcriptional changes and memory-like functional capacity of malaria pre-exposed γδ T cells using a <i>Plasmodium</i><i ...[more]

PMID: 33154754

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Project description:Immune homeostasis in tissues is achieved through a delicate balance between pathogenic T-cell responses directed at tissue-specific antigens and the ability of the tissue to inhibit these responses. The mechanisms by which tissues and the immune system communicate to establish and maintain immune homeostasis are currently unknown. Clinical evidence suggests that chronic or repeated exposure to self antigen within tissues leads to an attenuation of pathological autoimmune responses, possibly as a means to mitigate inflammatory damage and preserve function. Many human organ-specific autoimmune diseases are characterized by the initial presentation of the disease being the most severe, with subsequent flares being of lesser severity and duration. In fact, these diseases often spontaneously resolve, despite persistent tissue autoantigen expression. In the practice of antigen-specific immunotherapy, allergens or self antigens are repeatedly injected in the skin, with a diminution of the inflammatory response occurring after each successive exposure. Although these findings indicate that tissues acquire the ability to attenuate autoimmune reactions upon repeated responses to antigens, the mechanism by which this occurs is unknown. Here we show that upon expression of self antigen in a peripheral tissue, thymus-derived regulatory T cells (T(reg) cells) become activated, proliferate and differentiate into more potent suppressors, which mediate resolution of organ-specific autoimmunity in mice. After resolution of the inflammatory response, activated T(reg) cells are maintained in the target tissue and are primed to attenuate subsequent autoimmune reactions when antigen is re-expressed. Thus, T(reg) cells function to confer 'regulatory memory' to the target tissue. These findings provide a framework for understanding how T(reg) cells respond when exposed to self antigen in peripheral tissues and offer mechanistic insight into how tissues regulate autoimmunity.

Project description:BackgroundDuring intra-erythrocytic development, late asexually replicating Plasmodium falciparum parasites sequester from peripheral circulation. This facilitates chronic infection and is linked to severe disease and organ-specific pathology including cerebral and placental malaria. Immature gametocytes - sexual stage precursor cells - likewise disappear from circulation. Recent work has demonstrated that these sexual stage parasites are located in the hematopoietic system of the bone marrow before mature gametocytes are released into the bloodstream to facilitate mosquito transmission. However, as sequestration occurs only in vivo and not during in vitro culture, the mechanisms by which it is regulated and enacted (particularly by the gametocyte stage) remain poorly understood.ResultsWe generated the most comprehensive P. falciparum functional gene network to date by integrating global transcriptional data from a large set of asexual and sexual in vitro samples, patient-derived in vivo samples, and a new set of in vitro samples profiling sexual commitment. We defined more than 250 functional modules (clusters) of genes that are co-expressed primarily during the intra-erythrocytic parasite cycle, including 35 during sexual commitment and gametocyte development. Comparing the in vivo and in vitro datasets allowed us, for the first time, to map the time point of asexual parasite sequestration in patients to 22 hours post-invasion, confirming previous in vitro observations on the dynamics of host cell modification and cytoadherence. Moreover, we were able to define the properties of gametocyte sequestration, demonstrating the presence of two circulating gametocyte populations: gametocyte rings between 0 and approximately 30 hours post-invasion and mature gametocytes after around 7 days post-invasion.ConclusionsThis study provides a bioinformatics resource for the functional elucidation of parasite life cycle dynamics and specifically demonstrates the presence of the gametocyte ring stages in circulation, adding significantly to our understanding of the dynamics of gametocyte sequestration in vivo.

Dataset Information

Transcriptional Memory-Like Imprints and Enhanced Functional Activity in ?? T Cells Following Resolution of Malaria Infection.

Publications

Transcriptional Memory-Like Imprints and Enhanced Functional Activity in γδ T Cells Following Resolution of Malaria Infection.

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