The Identity of Human Tissue-Emigrant CD8+ T Cells

Buggert, Marcus; Vella, Laura A.; Nguyen, Son; Wu, Vincent H.; Chen, Zeyu; Sekine, Takuya; Perez‐Potti, André; Maldini, Colby R.; Manne, Sasikanth; Darko, Samuel; Ransier, Amy; Kuri-Cervantes, Leticia; Japp, Alberto Sada; Brody, Irene Bukh; Ivarsson, Martin A.; Gorin, Jean Baptiste; Rivera‐Ballesteros, Olga; Hertwig, Laura; Antel, Jack; Johnson, Matthew E.; Okoye, Afam A.; Picker, Louis J.; Vahedi, Golnaz; Sparrelid, Ernesto; Llewellyn-Lacey, Sian; Gostick, Emma; Sandberg, Johan K.; Björkström, Niklas K.; Bar‐Or, Amit; Dori, Yoav; Naji, Ali; Canaday, David H.; Laufer, Terri M.; Wells, Andrew D.; Price, David A.; Frank, Ian; Douek, Daniel C.; Wherry, E. John; Itkin, Maxim; Betts, Michael R.

doi:10.1016/j.cell.2020.11.019

Cited by 63 publications

(67 citation statements)

References 73 publications

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“…The edit distance results further show that blood-derived TCR clones segreagate distinct from clones in tissue sites. A recent study also showed that memory CD8 + T cell clones in blood were distinct from those circulating through the lymphatics which could transit through tissues [ 50 ]. Promoting TRM-mediated protection in mouse models requires site specific, rather than systemic priming [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

Maintenance of the human memory T cell repertoire by subset and tissue site

et al. 2021

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Background Immune-mediated protection is mediated by T cells expressing pathogen-specific T cell antigen receptors (TCR) that are maintained at diverse sites of infection as tissue-resident memory T cells (TRM) or that disseminate as circulating effector-memory (TEM), central memory (TCM), or terminal effector (TEMRA) subsets in blood and tissues. The relationship between circulating and tissue resident T cell subsets in humans remains elusive, and is important for promoting site-specific protective immunity. Methods We analyzed the TCR repertoire of the major memory CD4+ and CD8+T cell subsets (TEM, TCM, TEMRA, and TRM) isolated from blood and/or lymphoid organs (spleen, lymph nodes, bone marrow) and lungs of nine organ donors, and blood of three living individuals spanning five decades of life. High-throughput sequencing of the variable (V) portion of individual TCR genes for each subset, tissue, and individual were analyzed for clonal diversity, expansion and overlap between lineage, T cell subsets, and anatomic sites. TCR repertoires were further analyzed for TRBV gene usage and CDR3 edit distance. Results Across blood, lymphoid organs, and lungs, human memory, and effector CD8+T cells exhibit greater clonal expansion and distinct TRBV usage compared to CD4+T cell subsets. Extensive sharing of clones between tissues was observed for CD8+T cells; large clones specific to TEMRA cells were present in all sites, while TEM cells contained clones shared between sites and with TRM. For CD4+T cells, TEM clones exhibited the most sharing between sites, followed by TRM, while TCM clones were diverse with minimal sharing between sites and subsets. Within sites, TRM clones exhibited tissue-specific expansions, and maintained clonal diversity with age, compared to age-associated clonal expansions in circulating memory subsets. Edit distance analysis revealed tissue-specific biases in clonal similarity. Conclusions Our results show that the human memory T cell repertoire comprises clones which persist across sites and subsets, along with clones that are more restricted to certain subsets and/or tissue sites. We also provide evidence that the tissue plays a key role in maintaining memory T cells over age, bolstering the rationale for site-specific targeting of memory reservoirs in vaccines and immunotherapies.

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Section: Discussionmentioning

confidence: 99%

Maintenance of the human memory T cell repertoire by subset and tissue site

et al. 2021

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“…This lack of consensus might be partially driven by differences in epitope filtering and/or ranking between the different teams and suggest that efforts to harmonize neoantigen-prediction will be necessary for future clinical cross-comparison of neoantigen-based TIL trials between different centres. 92 Moreover, despite mutations that poorly bind to HLA-II being positively selected for during tumorigenesis, thus emphasising the importance of CD4 + T cells in anti-tumour immunity, 93 the computational prediction and analysis of HLA-II remains an ongoing challenge owing to the highly polymorphic nature of the HLA-II and poorly characterised endosomal HLA-II peptide processing, which limits the development of HLA-II peptide processing algorithms. 45 , 94 , 95 Furthermore, despite the core binding motif of both HLA molecules comprising peptides of approximately nine amino acids, HLA-II-restricted ones have a wider length range (11–20 amino acids) compared with HLA-I-restricted ones (8–11 amino acids) 96 which can make bioinformatics prediction task challenging.…”

Section: Cancer Genomicsmentioning

confidence: 99%

Promises and challenges of adoptive T-cell therapies for solid tumours

et al. 2021

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Cancer is a leading cause of death worldwide and, despite new targeted therapies and immunotherapies, many patients with advanced-stage- or high-risk cancers still die, owing to metastatic disease. Adoptive T-cell therapy, involving the autologous or allogeneic transplant of tumour-infiltrating lymphocytes or genetically modified T cells expressing novel T-cell receptors or chimeric antigen receptors, has shown promise in the treatment of cancer patients, leading to durable responses and, in some cases, cure. Technological advances in genomics, computational biology, immunology and cell manufacturing have brought the aspiration of individualised therapies for cancer patients closer to reality. This new era of cell-based individualised therapeutics challenges the traditional standards of therapeutic interventions and provides opportunities for a paradigm shift in our approach to cancer therapy. Invited speakers at a 2020 symposium discussed three areas—cancer genomics, cancer immunology and cell-therapy manufacturing—that are essential to the effective translation of T-cell therapies in the treatment of solid malignancies. Key advances have been made in understanding genetic intratumour heterogeneity, and strategies to accurately identify neoantigens, overcome T-cell exhaustion and circumvent tumour immunosuppression after cell-therapy infusion are being developed. Advances are being made in cell-manufacturing approaches that have the potential to establish cell-therapies as credible therapeutic options. T-cell therapies face many challenges but hold great promise for improving clinical outcomes for patients with solid tumours.

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“…Moreover, the expression of various genes involved in CD8 + T cell cytotoxicity, such as those encoding other granzymes and the death receptors Fas and TRAIL, were similarly lower in the lymph node CD8 + T cells from ECs. Recently, HIV-specific CD8 + T cells with a noncytotoxic T TM phenotype were detected more frequently in the thoracic ducts than in the blood ( 435 ).…”

Section: (X) Approaches To Identify Cafmentioning

confidence: 99%

The CD8⁺T Cell Noncytotoxic Antiviral Responses

Morvan

Teque

Locher³

et al. 2021

Microbiol Mol Biol Rev

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SUMMARY The CD8+ T cell noncytotoxic antiviral response (CNAR) was discovered during studies of asymptomatic HIV-infected subjects more than 30 years ago. In contrast to CD8+ T cell cytotoxic lymphocyte (CTL) activity, CNAR suppresses HIV replication without target cell killing. This activity has characteristics of innate immunity: it acts on all retroviruses and thus is neither epitope specific nor HLA restricted. The HIV-associated CNAR does not affect other virus families. It is mediated, at least in part, by a CD8+ T cell antiviral factor (CAF) that blocks HIV transcription. A variety of assays used to measure CNAR/CAF and the effects on other retrovirus infections are described. Notably, CD8+ T cell noncytotoxic antiviral responses have now been observed with other virus families but are mediated by different cytokines. Characterizing the protein structure of CAF has been challenging despite many biologic, immunologic, and molecular studies. It represents a low-abundance protein that may be identified by future next-generation sequencing approaches. Since CNAR/CAF is a natural noncytotoxic activity, it could provide promising strategies for HIV/AIDS therapy, cure, and prevention.

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The Identity of Human Tissue-Emigrant CD8+ T Cells

Cited by 63 publications

References 73 publications

Maintenance of the human memory T cell repertoire by subset and tissue site

Maintenance of the human memory T cell repertoire by subset and tissue site

Promises and challenges of adoptive T-cell therapies for solid tumours

The CD8⁺T Cell Noncytotoxic Antiviral Responses

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The Identity of Human Tissue-Emigrant CD8+ T Cells

Cited by 63 publications

References 73 publications

Maintenance of the human memory T cell repertoire by subset and tissue site

Maintenance of the human memory T cell repertoire by subset and tissue site

Promises and challenges of adoptive T-cell therapies for solid tumours

The CD8+T Cell Noncytotoxic Antiviral Responses

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The CD8⁺T Cell Noncytotoxic Antiviral Responses