Human MAIT-cell responses toEscherichia coli: activation, cytokine production, proliferation, and cytotoxicity

Mucosal-Associated Invariant T (MAIT) cells have been shown to play protective roles during infection with diverse pathogens through their propensity for rapid innate-like cytokine production and cytotoxicity. Among the potential applications for MAIT cells is to defend against Staphylococcus aureus, a pathogen of serious clinical significance. However, it is unknown how MAIT cell responses to S. aureus are elicited, nor has it been investigated whether MAIT cell cytotoxicity is mobilized against intracellular S. aureus. In this study, we investigate the capacity of human MAIT cells to respond directly to S. aureus. MAIT cells co-cultured with dendritic cells (DCs) infected with S. aureus rapidly upregulate CD69, express IFNγ and Granzyme B and degranulate. DC secretion of IL-12, but not IL-18, was implicated in this immune response, while TCR binding of MR1 is required to commence cytokine production. MAIT cell cytotoxicity resulted in apoptosis of S. aureus-infected cells, and reduced intracellular persistence of S. aureus. These findings implicate these unconventional T cells in important, rapid anti-S. aureus responses that may be of great relevance to the ongoing development of novel anti-S. aureus treatments.

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Regulation of Cytokine Production in T-Cell Responses to Inhalant Allergen:GATA-3 Expression Distinguishesbetween Th1- and Th2-Polarized Immunity

International Archives of Allergy and Immunology ◽

10.1159/000053703 ◽

2001 ◽

Vol 124 (1-3) ◽

pp. 176-179 ◽

Cited By ~ 13

Author(s):

Claudia Macaubas ◽

Patrick G. Holt

Keyword(s):

T Cell ◽

Cytokine Production ◽

T Cell Responses ◽

Cell Responses ◽

Th1 And Th2

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Perfect adaptation of CD8+ T cell responses to constant antigen input over a wide range of affinity is overcome by costimulation

10.1101/535385 ◽

2019 ◽

Cited By ~ 3

Author(s):

Nicola Trendel ◽

Philipp Kruger ◽

Stephanie Gaglione ◽

John Nguyen ◽

Johannes Pettmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cytokine Production ◽

Mechanistic Model ◽

T Cell Responses ◽

Dependent Manner ◽

Antigen Stimulation ◽

Cell Responses ◽

Perfect Adaptation ◽

Wide Range

AbstractMaintaining and limiting T cell responses to constant antigen stimulation is critical to control pathogens and maintain self-tolerance, respectively. Antigen recognition by T cell receptors (TCRs) induces signalling that activates T cells to produce cytokines and also leads to the downregulation of surface TCRs. In other systems, receptor downregulation can induce perfect adaptation to constant stimulation by a mechanism known as state-dependent inactivation that requires complete downregulation of the receptor or the ligand. However, this is not the case for the TCR, and therefore, precisely how TCR downregulation maintains or limits T cell responses is controversial. Here, we observed that in vitro expanded primary human T cells exhibit perfect adaptation in cytokine production to constant antigen stimulation across a 100,000-fold variation in affinity with partial TCR downregulation. By directly fitting a mechanistic model to the data, we show that TCR downregulation produces imperfect adaptation, but when coupled to a switch produces perfect adaptation in cytokine production. A pre-diction of the model is that pMHC-induced TCR signalling continues after adaptation and this is confirmed by showing that, while costimulation cannot prevent adaptation, CD28 and 4-1BB signalling reactivated adapted T cells to produce cytokines in a pMHC-dependent manner. We show that adaptation also applied to 1st generation chimeric antigen receptor (CAR)-T cells but is partially avoided in 2nd generation CARs. These findings high-light that even partial TCR downregulation can limit T cell responses by producing perfect adaptation rendering T cells dependent on costimulation for sustained responses.

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Sustained IFN-I stimulation impairs MAIT cell responses to bacteria by inducing IL-10 during chronic HIV-1 infection

Science Advances ◽

10.1126/sciadv.aaz0374 ◽

2020 ◽

Vol 6 (8) ◽

pp. eaaz0374 ◽

Cited By ~ 4

Author(s):

X. Tang ◽

S. Zhang ◽

Q. Peng ◽

L. Ling ◽

H. Shi ◽

...

Keyword(s):

Cell Activation ◽

Surface Protein ◽

Interleukin 10 ◽

Mait Cells ◽

Cell Dysfunction ◽

Cell Responses ◽

High Level ◽

Hiv 1 ◽

Mait Cell

Mucosal-associated invariant T (MAIT) cells in HIV-1–infected individuals are functionally impaired by poorly understood mechanisms. Single-cell transcriptional and surface protein analyses revealed that peripheral MAIT cells from HIV-1–infected subjects were highly activated with the up-regulation of interferon (IFN)–stimulated genes as compared to healthy individuals. Sustained IFN-α treatment suppressed MAIT cell responses to Escherichia coli by triggering high-level interleukin-10 (IL-10) production by monocytes, which subsequently inhibited the secretion of IL-12, a crucial costimulatory cytokine for MAIT cell activation. Blocking IFN-α or IL-10 receptors prevented MAIT cell dysfunction induced by HIV-1 exposure in vitro. Moreover, blocking the IL-10 receptor significantly improved anti–Mycobacterium tuberculosis responses of MAIT cells from HIV-1–infected patients. Our findings demonstrate the central role of the IFN-I/IL-10 axis in MAIT cell dysfunction during HIV-1 infection, which has implications for the development of anti–IFN-I/IL-10 strategies against bacterial coinfections in HIV-1–infected patients.

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Monitoring HIV-specific CD8+ T cell responses by intracellular cytokine production

Immunology Letters ◽

10.1016/s0165-2478(01)00273-5 ◽

2001 ◽

Vol 79 (1-2) ◽

pp. 117-125 ◽

Cited By ~ 47

Author(s):

Michael R Betts ◽

Joseph P Casazza ◽

Richard A Koup

Keyword(s):

T Cell ◽

Cytokine Production ◽

T Cell Responses ◽

Cd8 T Cell ◽

Intracellular Cytokine ◽

Cell Responses

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Vaccination of human subjects expands both specific and bystander memory T cells but antibody production remains vaccine specific

Blood ◽

10.1182/blood-2005-08-3255 ◽

2006 ◽

Vol 107 (7) ◽

pp. 2806-2813 ◽

Cited By ~ 51

Author(s):

Gianfranco Di Genova ◽

Joanna Roddick ◽

Feargal McNicholl ◽

Freda K. Stevenson

Keyword(s):

Antibody Production ◽

Protective Immunity ◽

Cytokine Production ◽

Human Subjects ◽

Cellular Responses ◽

T Helper ◽

Purified Protein Derivative ◽

Cell Responses ◽

Common Antigens

AbstractHuman subjects maintain long-term immunologic memory against infective organisms but the mechanism is unclear. CD4+ T-helper memory (Thmem) cells are pivotal in controlling humoral and cellular responses, therefore their longevity and response to vaccination are critical for maintenance of protective immunity. To probe the dynamics of the Thmem-cell response to antigenic challenge, we investigated subjects following a booster injection with tetanus toxoid (TT). Expansion of TT-specific Thmem cells and cytokine production showed complex kinetics. Strikingly, parallel expansion and cytokine production occurred in pre-existing Thmem cells specific for 2 other common antigens: purified protein derivative of tuberculin and Candida albicans. Bystander expansion occurred in Thmem but not in Thnaive cells. Antibody production against TT peaked approximately 2 weeks after vaccination and gradually declined. However, pre-existing antibody against the other antigens did not change. It appears that although all Thmem cells are readily stimulated to expand, antibody responses are controlled by antigen availability. These findings relate to the maintenance of memory and have consequences for assessments of specific T-cell responses to vaccination.

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Multiple layers of heterogeneity and subset diversity in human MAIT cell responses to distinct microorganisms and to innate cytokines

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1705759114 ◽

2017 ◽

Vol 114 (27) ◽

pp. E5434-E5443 ◽

Cited By ~ 102

Author(s):

Joana Dias ◽

Edwin Leeansyah ◽

Johan K. Sandberg

Keyword(s):

Killer Cell ◽

Cell Subset ◽

Effector Memory ◽

Response Patterns ◽

E Coli ◽

Mait Cells ◽

Cell Responses ◽

Fungal Organisms ◽

Subset Diversity ◽

Mait Cell

Mucosa-associated invariant T (MAIT) cells are a large innate-like T-cell subset in humans defined by invariant TCR Vα7.2 use and expression of CD161. MAIT cells recognize microbial riboflavin metabolites of bacterial or fungal origin presented by the monomorphic MR1 molecule. The extraordinary level of evolutionary conservation of MR1 and the limited known diversity of riboflavin metabolite antigens have suggested that MAIT cells are relatively homogeneous and uniform in responses against diverse microbes carrying the riboflavin biosynthesis pathway. The ability of MAIT cells to exhibit microbe-specific functional specialization has not been thoroughly investigated. Here, we found that MAIT cell responses against Escherichia coli and Candida albicans displayed microbe-specific polyfunctional response profiles, antigen sensitivity, and response magnitudes. MAIT cell effector responses against E. coli and C. albicans displayed differential MR1 dependency and TCR β-chain bias, consistent with possible divergent antigen subspecificities between these bacterial and fungal organisms. Finally, although the MAIT cell immunoproteome was overall relatively homogenous and consistent with an effector memory-like profile, it still revealed diversity in a set of natural killer cell-associated receptors. Among these, CD56, CD84, and CD94 defined a subset with higher expression of the transcription factors promyelocytic leukemia zinc finger (PLZF), eomesodermin, and T-bet and enhanced capacity to respond to IL-12 and IL-18 stimulation. Thus, the conserved and innate-like MAIT cells harbor multiple layers of functional heterogeneity as they respond to bacterial or fungal organisms or innate cytokines and adapt their antimicrobial response patterns in a stimulus-specific manner.

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Mast Cells Modulate Antigen-Specific CD8+ T Cell Activation During LCMV Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.688347 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yana Hackler ◽

Frank Siebenhaar ◽

Max Löhning ◽

Marcus Maurer ◽

Melba Muñoz

Keyword(s):

T Cells ◽

T Cell ◽

Mast Cells ◽

Immune Responses ◽

Cytokine Production ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Deficient Mice ◽

Lcmv Infection

Mast cells (MCs), strategically localized at mucosal surfaces, provide first-line defense against pathogens and shape innate and adaptive immune responses. Recent studies have shown that MCs are involved in pathogenic responses to several viruses including herpes simplex viruses, dengue virus, vaccinia virus and influenza virus. However, the underlying mechanisms of MCs in the activation of CD8+ T cells during viral infections are not fully understood. Therefore, we investigate the role of MCs in the development of virus-specific CD8+ T cell responses using the well-characterized murine lymphocytic choriomeningitis virus (LCMV) model and the transgenic MasTRECK mice that contain the human diphtheria toxin receptor as an inducible MC-deficient model. Here, we report that MCs are essential for the activation and expansion of virus-specific CD8+ T cells. After MC depletion and subsequent intradermal LCMV infection, the CD8+ T cell effector phenotype and antiviral cytokine production were impaired at the peak of infection (day 8 p.i.). Importantly, MC-deficient mice were unable to control the infection and exhibited significantly higher viral loads in the spleen and in the ear draining lymph nodes compared to that of wild type control mice. In the absence of MCs, dendritic cell (DC) activation was impaired upon LCMV infection. In addition, type-I interferon (IFN) levels in the serum and in the spleen of MC-deficient mice were reduced during the first days of infection. Interestingly, depletion of MCs after intradermal LCMV infection did not impair virus-specific CD8+ T cell expansion, activation or antiviral cytokine production. In summary, our results indicate that MCs play a pivotal role in the activation and antiviral functions of CD8+ T cells through proper DC activation. A better understanding of the impact of MCs on CD8+ T cell responses is mandatory to improve antiviral immune responses.

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Identification of VIMP as a gene inhibiting cytokine production in human CD4+ effector T cells

10.1101/2020.07.06.189456 ◽

2020 ◽

Author(s):

Christophe Capelle ◽

Ni Zeng ◽

Egle Danileviciute ◽

Sabrina Freitas Rodrigues ◽

Markus Ollert ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cd4 T Cells ◽

Cytokine Production ◽

Effector T Cells ◽

Effector Functions ◽

Cell Responses ◽

Critical Nodes ◽

Promising Therapeutic Target ◽

Genes Encoding

AbstractMany players regulating the CD4+ T cell-mediated inflammatory response have already been identified. However, the critical nodes that constitute the regulatory and signalling networks underlying CD4 T cell responses are still missing. Using a correlation network-guided strategy based on time-series transcriptome data of human CD4+CD25- effector T cells (Teffs), here we identified VIMP (VCP-interacting membrane protein), one of the 25 genes encoding selenocysteine in humans, as a gene regulating the effector functions of human CD4 T cells. Knocking-down VIMP in Teffs enhanced their proliferation and expression of several cytokines, including IL-2 and CSF2. We identified VIMP as an endogenous inhibitor of cytokine production in Teffs via both, the E2F5 transcription regulatory pathway and the Ca2+/NFATC2 signalling pathway. Our work not only indicates that VIMP might be a promising therapeutic target for various diseases involving CD4 T cells, but also shows that our network-guided approach might be generally applicable to different types of cells and can significantly aid in predicting new functions of the genes of interest.One-sentence summaryUsing a network-guided approach, we identified that Selenoprotein S (SELS or VIMP) negatively regulates cytokine expression of human CD4+ effector T cells via the E2F5 and calcium Ca2+/NFATC2 pathways.

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Cysticercus cellulosae Regulates T-Cell Responses and Interacts With the Host Immune System by Excreting and Secreting Antigens

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2021.728222 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xianmin Fan ◽

Yue Zhang ◽

Renhui Ouyang ◽

Bo Luo ◽

Lizhu Li ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Immune Responses ◽

Cytokine Production ◽

Host Immune Response ◽

Interleukin 10 ◽

Host Immune System ◽

Cell Responses ◽

Cysticercus Cellulosae ◽

T Cell Immune Responses

Cysticercus cellulosae (C. cellulosae) excretes and secretes antigens during the parasitic process to regulate the host immune response; however, resulting immune response and cytokine production in the host during infection still remains unclear. We used C. cellulosae crude antigens (CAs) as controls to explore the effect of excretory secretory antigens (ESAs) on T-cell immune responses in piglets. C. cellulosae ESAs induced imbalanced CD4+/CD8+ T-cell proportions, increased the CD4+Foxp3+ and CD8+Foxp3+ T-cell frequencies, and induced lymphocytes to produce interleukin-10, which was mainly attributed to CD4+ and CD4−CD8− T cells. The ESAs also induced Th2-type immune responses. The results showed that the ability of C. cellulosae to escape the host immune attacks and establish a persistent infection may be related to host immune response regulation by the ESAs.

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