Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance

Sallusto, Federica; Geginat, Jens; Lanzavecchia, Antonio

doi:10.1146/annurev.immunol.22.012703.104702

Cited by 2,574 publications

(2,505 citation statements)

References 123 publications

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“…This is not unexpected given that the primary role of both terminally differentiated and effector memory cytotoxic T cells is to facilitate direct target cell destruction or rapid generation of effector killer cells, respectively. Both subpopulations contain abundant lytic granules harbouring granzymes and perforins, but Temra T cells have been reported to harbour the highest amounts 24. In this study, we show that granzyme B is present in CD8 + T cells with levels rising with increasing concentration of ImmTAC.…”

Section: Discussionmentioning

confidence: 46%

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

et al. 2017

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SummaryThe success of immune system‐based cancer therapies depends on a broad immune response engaging a range of effector cells and mechanisms. Immune mobilizing monoclonal T cell receptors (TCRs) against cancer (ImmTAC™ molecules: fusion proteins consisting of a soluble, affinity enhanced TCR and an anti‐CD3 scFv antibody) were previously shown to redirect CD8+ and CD4+ T cells against tumours. Here we present evidence that IMCgp100 (ImmTAC recognizing a peptide derived from the melanoma‐specific protein, gp100, presented by HLA‐A*0201) efficiently redirects and activates effector and memory cells from both CD8+ and CD4+ repertoires. Using isolated subpopulations of T cells, we find that both terminally differentiated and effector memory CD8+ T cells redirected by IMCgp100 are potent killers of melanoma cells. Furthermore, CD4+ effector memory T cells elicit potent cytotoxic activity leading to melanoma cell killing upon redirection by IMCgp100. The majority of T cell subsets belonging to both the CD8+ and CD4+ repertoires secrete key pro‐inflammatory cytokines (tumour necrosis factor‐α, interferon‐γ, interleukin‐6) and chemokines (macrophage inflammatory protein‐1α‐β, interferon‐γ‐inducible protein‐10, monocyte chemoattractant protein‐1). At an individual cell level, IMCgp100‐redirected T cells display a polyfunctional phenotype, which is a hallmark of a potent anti‐cancer response. This study demonstrates that IMCgp100 induces broad immune responses that extend beyond the induction of CD8+ T cell‐mediated cytotoxicity. These findings are of particular importance because IMCgp100 is currently undergoing clinical trials as a single agent or in combination with check point inhibitors for patients with malignant melanoma.

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Section: Discussionmentioning

confidence: 46%

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

et al. 2017

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“…5d). Although we could see that terminally differentiated T EMRA cells displayed the lowest DNA methylation in the PRF1 locus, leading to consequently higher perforin expression compared to T RM cells, we know that T EMRA cells are short‐lived in contrast to T RM cells [30]. Moreover, long‐lived T RM cells are demonstrated to elicit more potent local immune protection in the tissue against infection [31].…”

Section: Discussionmentioning

confidence: 99%

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Hartana

Bergman

Broomé

et al. 2018

Clinical and Experimental Immunology

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SummaryTissue‐resident memory T (TRM) cells are CD8+ T lymphocytes that reside in the tissues, including tumours. This T cell subset possesses a magnitude of cytotoxicity, but its epigenetic regulation has not been studied. Here, we investigate the impact of perforin DNA methylation in TRM cells and correlate it with their functional potential. Fifty‐three urothelial urinary bladder cancer (UBC) patients were recruited prospectively. The DNA methylation status of the perforin gene (PRF1) locus in TRM cells was investigated by pyrosequencing. Flow cytometry with ViSNE analysis and in‐vitro stimulation were used to evaluate TRM cell phenotypes. We discovered that tumour TRM cells have low DNA methylation in the PRF1 locus (32·9% methylation), which corresponds to increased numbers of perforin‐expressing TRM cells. Surprisingly, programmed cell death 1 (PD‐1) expression is high in tumour TRM cells, suggesting exhaustion. Following interleukin‐15 and T cell receptor stimulation, perforin and T‐bet expressions are enhanced, indicating that TRM cells from tumours are not terminally exhausted. Moreover, a high number of TRM cells infiltrating the tumours corresponds to lower tumour stage in patients. In conclusion, TRM cells from UBC tumours are epigenetically cytotoxic with signs of exhaustion. This finding identifies TRM cells as potential new targets for cancer immunotherapy.

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“…T cells are critical components of the adaptive immune system that provide specific long‐lasting protection against pathogens (Sallusto, Geginat & Lanzavecchia, 2004). Naïve T cells generated in the thymus migrate to lymphoid tissues throughout the body.…”

Section: Introductionmentioning

confidence: 99%

Aging impacts CD103⁺CD8⁺ T cell presence and induction by dendritic cells in the genital tract

et al. 2018

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SummaryAs women age, susceptibility to systemic and genital infections increases. Tissue‐resident memory T cells (TRMs) are CD103+ CD8+ long‐lived lymphocytes that provide critical mucosal immune protection. Mucosal dendritic cells (DCs) are known to induce CD103 expression on CD8+ T cells. While CD103+ CD8+ T cells are found throughout the female reproductive tract (FRT), the extent to which aging impacts their presence and induction by DCs remains unknown. Using hysterectomy tissues, we found that endometrial CD103+ CD8+ T cells were increased in postmenopausal compared to premenopausal women. Endometrial DCs from postmenopausal women were significantly more effective at inducing CD103 expression on allogeneic naïve CD8+ T cells than DCs from premenopausal women; CD103 upregulation was mediated through membrane‐bound TGFβ signaling. In contrast, cervical CD103+ T cells and DC numbers declined in postmenopausal women with age. Decreases in DCs correlated with decreased CD103+ T cells in endocervix, but not ectocervix. Our findings demonstrate a previously unrecognized compartmentalization of TRMs in the FRT of postmenopausal women, with loss of TRMs and DCs in the cervix with aging, and increased TRMs and DC induction capacity in the endometrium. These findings are relevant to understanding immune protection in the FRT and to the design of vaccines for women of all ages.

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Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance

Cited by 2,574 publications

References 123 publications

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Aging impacts CD103⁺CD8⁺ T cell presence and induction by dendritic cells in the genital tract

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Central Memory and Effector Memory T Cell Subsets: Function, Generation, and Maintenance

Cited by 2,574 publications

References 123 publications

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

Tissue-resident memory T cells are epigenetically cytotoxic with signs of exhaustion in human urinary bladder cancer

Aging impacts CD103+CD8+ T cell presence and induction by dendritic cells in the genital tract

Contact Info

Product

Resources

About

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8⁺ and CD4⁺ T cells

Aging impacts CD103⁺CD8⁺ T cell presence and induction by dendritic cells in the genital tract