Affinity-matured HLA class II dimers for robust staining of antigen-specific CD4+ T cells

Sugata, Kenji; Matsunaga, Yukiko; Yamashita, Yūki; Nakatsugawa, Munehide; Guo, Tingxi; Halabelian, L.; Ohashi, Yota; Saso, Kayoko; Rahman, Muhammed A.; Anczurowski, Mark; Wang, Chung-Hsi; Murata, Kenji; Shinmoto, Hiroshi; Kagoya, Yuki; Ly, Dalam; Burt, Brian D; Butler, Marcus O.; Mak, Tak W.; Hirano, Naoto

doi:10.1038/s41587-021-00836-4

Cited by 17 publications

(23 citation statements)

References 54 publications

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“…It is reported that only certain alleles of the HLA class II genes allow the presentation of endogenous peptides to T-cells, and that HLA-DP molecules with β-chains encoding Gly84 (DP84Gly), such as DP2 and DP4, can present antigen to T-cells(26). Therefore, we used an in vitro model of TCR stimulation through HLA class II utilizing an HLA-DP4-restricted TCR (Clone 9) which is specific to the cancer testis antigen WT1 (Wilms tumor protein-1)(27) to assess the antigen presentation capability of HTLV-1-infected CD4 + T cells. In fact, HLA-DP4-expressing and WT1 peptide-pulsed HTLV-1-infected cell lines induced cytokine production in responder T-cells that carry Clone 9 TCR while HTLV-1 negative T-cell lines did not (Figure 6A).…”

Section: Resultsmentioning

confidence: 99%

Retrovirus-induced leukemia – hijack of T-cell activation mechanisms revealed by single-cell analysis

Tan

Sugata

Reda

et al. 2021

Preprint

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Human T-cell leukemia virus type 1 (HTLV-1) mainly infects CD4+ T-cells and induces chronic, persistent infection in infected individuals with some progressing to develop adult T-cell leukemia/lymphoma (ATL). Whilst HTLV-1 alters cellular differentiation, activation and survival, it is unknown whether and how these changes contribute to malignant transformation of infected T-cells. In this study, we used single-cell RNA-Seq and TCR-Seq to investigate T-cell differentiation and HTLV-1-mediated transformation processes. We analyzed 87,742 single cells from peripheral blood of 12 infected and 3 uninfected individuals. Using multiple independent bioinformatic methods, we demonstrated that naive T-cells dynamically change into activated T-cells including infected cells, which seamlessly transitioned into ATL cells characterized by clonally expanded, highly-activated T-cells. Notably, the more activated ATL cells are, the more they acquire Treg signatures. Intriguingly, HLA class II genes were uniquely induced in infected cells, further upregulated in ATL cells and was induced by viral protein Tax. Functional assays revealed that by upregulating HLA class II, HTLV-1-infected cells can act as tolerogenic antigen presenting cells (APCs) to induce anergy of antigen specific T-cells. In conclusion, our study revealed the in vivo mechanisms of HTLV-1-mediated transformation and immune escape at single-cell level.

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Section: Resultsmentioning

confidence: 99%

Retrovirus-induced leukemia – hijack of T-cell activation mechanisms revealed by single-cell analysis

Tan

Sugata

Reda

et al. 2021

Preprint

Self Cite

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“…The bacteria–host interaction model helps in the discovery of molecules with biologically relevant effects in diseases other than UTI. In addition to producing molecules that directly affect virulence, UPEC strains were shown to inhibit and degrade the MYC oncogene protein 146 . Cancer cells are fast growing, outcompete non-malignant cells and spread to distant sites, where they cause metastasis 147 .…”

Section: Acute Pyelonephritismentioning

confidence: 99%

Section: Acute Pyelonephritismentioning

confidence: 99%

“…Surprisingly, UPEC strains deplete MYC protein from infected cells and tissues as a result of accelerated MYC protein degradation and attenuated MYC expression 146 . This bacterial strategy was translated to cancer therapy, demonstrating that Lon protease treatment is efficacious in slowing cancer progression and increasing survival 146 . The bacterial Lon protease is shown to rapidly degrade MYC without affecting MAX and other upstream regulators such as AKT, CDK9 or CPEB1, suggesting a high degree of specificity for MYC 146 .…”

Section: Acute Pyelonephritismentioning

confidence: 99%

“…The Lon protease is a conserved, ATP-dependent serine protease that maintains homeostasis in prokaryotes by processing short-lived regulatory proteins 152 . The Lon protease targets MYC in a variety of cancer cells 146 , including Burkitt lymphoma cells, in which MYC was first discovered 153 . Gene expression profiles in Lon-treated tissues showed a strong inhibitory effect on cancer-related genes, but no major effects on other gene categories, also supporting the potential of this therapeutic approach 146 .…”

Section: Acute Pyelonephritismentioning

confidence: 99%

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Molecular determinants of disease severity in urinary tract infection

et al. 2021

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The most common and lethal bacterial pathogens have co-evolved with the host. Pathogens are the aggressors, and the host immune system is responsible for the defence. However, immune responses can also become destructive, and excessive innate immune activation is a major cause of infection-associated morbidity, exemplified by symptomatic urinary tract infections (UTIs), which are caused, in part, by excessive innate immune activation. Severe kidney infections (acute pyelonephritis) are a major cause of morbidity and mortality, and painful infections of the urinary bladder (acute cystitis) can become debilitating in susceptible patients. Disease severity is controlled at specific innate immune checkpoints, and a detailed understanding of their functions is crucial for strategies to counter microbial aggression with novel treatment and prevention measures. One approach is the use of bacterial molecules that reprogramme the innate immune system, accelerating or inhibiting disease processes. A very different outcome is asymptomatic bacteriuria, defined by low host immune responsiveness to bacteria with attenuated virulence. This observation provides the rationale for immunomodulation as a new therapeutic tool to deliberately modify host susceptibility, control the host response and avoid severe disease. The power of innate immunity as an arbitrator of health and disease is also highly relevant for emerging pathogens, including the current COVID-19 pandemic.

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Recent advances in cancer immunotherapy

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Cancer immunotherapy represents a major advance in the cure of cancer following the dramatic advancements in the development and refinement of chemotherapies and radiotherapies. In the recent decades, together with the development of early diagnostic techniques, immunotherapy has significantly contributed to improving the survival of cancer patients. The immune-checkpoint blockade agents have been proven effective in a significant fraction of standard therapy refractory patients. Importantly, recent advances are providing alternative immunotherapeutic tools that could help overcome their limitations. In this mini review, we provide an overview on the main steps of the discovery of classic immune-checkpoint blockade agents and summarise the most recent development of novel immunotherapeutic strategies, such as tumour antigens, bispecific antibodies and TCR-engineered T cells.

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Affinity-matured HLA class II dimers for robust staining of antigen-specific CD4+ T cells

Cited by 17 publications

References 54 publications

Retrovirus-induced leukemia – hijack of T-cell activation mechanisms revealed by single-cell analysis

Retrovirus-induced leukemia – hijack of T-cell activation mechanisms revealed by single-cell analysis

Molecular determinants of disease severity in urinary tract infection

Recent advances in cancer immunotherapy

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