Bystander CD4+ T cells: crossroads between innate and adaptive immunity

Lee, Hong-Gyun; Cho, Min Zi; Choi, Je-Min

doi:10.1038/s12276-020-00486-7

Cited by 72 publications

(50 citation statements)

References 97 publications

(171 reference statements)

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“…This indicates that as early as 24h after interaction, Leishmania modulates adaptive immune cell functions in PBMCs from previously unexposed healthy individuals, revealing a largely unexplored and exploitable dimension of the host-pathogen interactome in Leishmania infections. The mechanism(s) mediating this rapid activation, especially of naïve T cells, remains to be determined, but could occur via bystander (antigen-independent) activation of naïve or memory T cells ( Kim and Shin, 2019 ; Lee et al, 2020 ), cross-reactivity of memory T cells, or potentially via antigen-presentation by circulating fibrocytes ( Chesney et al, 1997 ; Grab et al, 2004 ). Interestingly, bystander activation of Lysteria -specific and LCMV- specific memory T-cells has been reported in chronic L. donovani infection of Lysteria- immune mice ( Polley et al, 2005 ), and in acutely L. major infected mice, respectively ( Crosby et al, 2014 ).…”

Section: Resultsmentioning

confidence: 99%

Early Leukocyte Responses in Ex-Vivo Models of Healing and Non-Healing Human Leishmania (Viannia) panamensis Infections

Gómez

Belew

Navas

et al. 2021

Front. Cell. Infect. Microbiol.

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Early host-pathogen interactions drive the host response and shape the outcome of natural infections caused by intracellular microorganisms. These interactions involve a number of immune and non-immune cells and tissues, along with an assortment of host and pathogen-derived molecules. Our current knowledge has been predominantly derived from research on the relationships between the pathogens and the invaded host cell(s), limiting our understanding of how microbes elicit and modulate immunological responses at the organismal level. In this study, we explored the early host determinants of healing and non-healing responses in human cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) panamensis. We performed a comparative transcriptomic profiling of peripheral blood mononuclear cells from healthy donors (PBMCs, n=3) exposed to promastigotes isolated from patients with chronic (CHR, n=3) or self-healing (SH, n=3) CL, and compared these to human macrophage responses. Transcriptomes of L. V. panamensis-infected PBMCs showed enrichment of functional gene categories derived from innate as well as adaptive immune cells signatures, demonstrating that Leishmania modulates adaptive immune cell functions as early as after 24h post interaction with PBMCs from previously unexposed healthy individuals. Among differentially expressed PBMC genes, four broad categories were commonly modulated by SH and CHR strains: cell cycle/proliferation/differentiation, metabolism of macromolecules, immune signaling and vesicle trafficking/transport; the first two were predominantly downregulated, and the latter upregulated in SH and CHR as compared to uninfected samples. Type I IFN signaling genes were uniquely up-regulated in PBMCs infected with CHR strains, while genes involved in the immunological synapse were uniquely downregulated in SH infections. Similarly, pro-inflammatory response genes were upregulated in isolated macrophages infected with CHR strains. Our data demonstrate that early responses during Leishmania infection extend beyond innate cell and/or phagocytic host cell functions, opening new frontiers in our understanding of the triggers and drivers of human CL.

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Section: Resultsmentioning

confidence: 99%

Early Leukocyte Responses in Ex-Vivo Models of Healing and Non-Healing Human Leishmania (Viannia) panamensis Infections

Gómez

Belew

Navas

et al. 2021

Front. Cell. Infect. Microbiol.

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“…This observation was independent of the mode of stimulation, which represented activation of either innate (LPS) or adaptive (αCD3/CD28) immunity. Of note, it has been shown that innate inflammatory stimulation is capable of activating IL-22 production by (memory) CD4 + /CD8 + T cells through action of cytokines such as IL-1 [ 39 , 50 , 51 ]. In these same female splenocyte cultures in which enhanced IL-22 production was evident, sex-dependent regulation of IL-10, IFNγ, and TNFα was lacking, an observation again indicating specificity of IL-22 regulation.…”

Section: Discussionmentioning

confidence: 99%

Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product

Stülb

Bachmann

Gonther

et al. 2021

IJMS

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Gaining detailed knowledge about sex-related immunoregulation remains a crucial prerequisite for the development of adequate disease models and therapeutic strategies enabling personalized medicine. Here, the key parameter of the production of cytokines mediating disease resolution was investigated. Among these cytokines, STAT3-activating interleukin (IL)-22 is principally associated with recovery from tissue injury. By investigating paradigmatic acetaminophen-induced liver injury, we demonstrated that IL-22 expression is enhanced in female mice. Increased female IL-22 was confirmed at a cellular level using murine splenocytes stimulated by lipopolysaccharide or αCD3/CD28 to model innate or adaptive immunoactivation. Interestingly, testosterone or dihydrotestosterone reduced IL-22 production by female but not by male splenocytes. Mechanistic studies on PMA/PHA-stimulated T-cell-lymphoma EL-4 cells verified the capability of testosterone/dihydrotestosterone to reduce IL-22 production. Moreover, we demonstrated by chromatin immunoprecipitation that testosterone impairs binding of the aryl hydrocarbon receptor to xenobiotic responsive elements within the murine IL-22 promoter. Overall, female mice undergoing acute liver injury and cultured female splenocytes upon inflammatory activation display increased IL-22. This observation is likely related to the immunosuppressive effects of androgens in males. The data presented concur with more pronounced immunological alertness demonstrable in females, which may relate to the sex-specific course of some immunological disorders.

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“…CD4 + T cell depletion is the hallmark of the pathogenesis of HIV-1 and HIV-2 infection (42). However, the host immune system continuously exchanges dying CD4 + T cells with naïve CD4 + T cells during the early stages of HIV infection (43). Compared to HIV-1, HIV-2 is less pathogenic and is associated with a long asymptomatic phase after infection, reduced viral load and slower decline of CD4 + T cells (44,45).…”

Section: Discussionmentioning

confidence: 99%

Role of Circulating T Follicular Helper Cells and Stem-Like Memory CD4+ T Cells in the Pathogenesis of HIV-2 Infection and Disease Progression

et al. 2021

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CD4+ T cells are critical players in the host adaptive immune response. Emerging evidence suggests that certain CD4+ T cell subsets contribute significantly to the production of neutralizing antibodies and help in the control of virus replication. Circulating T follicular helper cells (Tfh) constitute a key T cell subset that triggers the adaptive immune response and stimulates the production of neutralizing antibodies (NAbs). T cells having stem cell-like property, called stem-like memory T cells (Tscm), constitute another important subset of T cells that play a critical role in slowing the rate of disease progression through the differentiation and expansion of different types of memory cell subsets. However, the role of these immune cell subsets in T cell homeostasis, CD4+ T cell proliferation, and progression of disease, particularly in HIV-2 infection, has not yet been elucidated. The present study involved a detailed evaluation of the different CD4+ T cell subsets in HIV-2 infected persons with a view to understanding the role of these immune cell subsets in the better control of virus replication and delayed disease progression that is characteristic of HIV-2 infection. We observed elevated levels of CD4+ Tfh and CD4+ Tscm cells along with memory and effector T cell abundance in HIV-2 infected individuals. We also found increased frequencies of CXCR5+ CD8+ T cells and CD8+ Tscm cells, as well as memory B cells that are responsible for NAb development in HIV-2 infected persons. Interestingly, we found that the frequency of memory CD4+ T cells as well as memory B cells correlated significantly with neutralizing antibody titers in HIV-2 infected persons. These observations point to a more robust CD4+ T cell response that supports B cell differentiation, antibody production, and CD8+ T cell development in HIV-2 infected persons and contributes to better control of the virus and slower rate of disease progression in these individuals.

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Bystander CD4+ T cells: crossroads between innate and adaptive immunity

Cited by 72 publications

References 97 publications

Early Leukocyte Responses in Ex-Vivo Models of Healing and Non-Healing Human Leishmania (Viannia) panamensis Infections

Early Leukocyte Responses in Ex-Vivo Models of Healing and Non-Healing Human Leishmania (Viannia) panamensis Infections

Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product

Role of Circulating T Follicular Helper Cells and Stem-Like Memory CD4+ T Cells in the Pathogenesis of HIV-2 Infection and Disease Progression

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