Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency

Schmueck-Henneresse, Michael; Sharaf, Radwa; Vogt, Katrin; Weist, Benjamin; Landwehr-Kenzel, Sybille; Fuehrer, Henrike; Jurisch, Anke; Babel, Nina; Rooney, Cliona M.; Reinke, Petra; Volk, Hans‐Dieter

doi:10.4049/jimmunol.1402090

Cited by 34 publications

(44 citation statements)

References 46 publications

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“…2). This subset is detectable in very low numbers among circulating human PBMCs [34,35]. In addition, an antigen-experienced but CD44 low memory T cell subset has been suggested as the murine homologue of human TSCMs [36,37].…”

Section: 3 Memory T Cell Ontogeny and Stemnessmentioning

confidence: 99%

Role of memory T cell subsets for adoptive immunotherapy

Busch

Fräßle

Sommermeyer

et al. 2016

Seminars in Immunology

176

186

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Adoptive transfer of primary (unmodified) or genetically engineered antigen-specific T cells has demonstrated astonishing clinical results in the treatment of infections and some malignancies. Besides the definition of optimal targets and antigen receptors, the differentiation status of transferred T cells is emerging as a crucial parameter for generating cell products with optimal efficacy and safety profiles. Long-living memory T cells subdivide into phenotypically as well as functionally different subsets (e.g. central memory, effector memory, tissue-resident memory T cells). This diversification process is crucial for effective immune protection, with probably distinct dependencies on the presence of individual subsets dependent on the disease to which the immune response is directed as well as its organ location. Adoptive T cell therapy intends to therapeutically transfer defined T cell immunity into patients. Efficacy of this approach often requires long-term maintenance of transferred cells, which depends on the presence and persistence of memory T cells. However, engraftment and survival of highly differentiated memory T cell subsets upon adoptive transfer is still difficult to achieve. Therefore, the recent observation that a distinct subset of weakly differentiated memory T cells shows all characteristics of adult tissue stem cells and can reconstitute all types of effector and memory T cell subsets, became highly relevant. We here review our current understanding of memory subset formation and T cell subset purification, and it's implications for adoptive immunotherapy.

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Section: 3 Memory T Cell Ontogeny and Stemnessmentioning

confidence: 99%

Role of memory T cell subsets for adoptive immunotherapy

Busch

Fräßle

Sommermeyer

et al. 2016

Seminars in Immunology

176

186

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“…Data regarding the best T-cell subset from which to derive CAR T-cells for infusion are inconclusive and controversial and most patients receive CD4 + and CD8 + T-cells whose subset derivation is unknown (2–4, 11–20). The ultimate objective of T-cell therapy is to transfer a long-lived T-cell population with the capacity to differentiate into potent tumor-specific effectors and to self-renew (8, 24). Short-lived effector T-cells (T EFF ) possess potent effector function in vitro , however, appear less attractive for adoptive immunotherapy because of their limited proliferation and engraftment in vivo (25–27).…”

Section: Introductionmentioning

confidence: 99%

“…Expression of the lymph node homing molecules CCR7 and the leucocyte common antigen (CD45) isoforms RA and RO distinguishes memory from naïve T-cells and allows the dissection of the memory/effector T-cell compartment at least into four main subsets (30, 31): Memory stem T-cells (T SCM ), central memory T-cells (T CM ), effector memory (T EM ) and terminally differentiated effector T-cells (T EMRA ) (24, 30, 31). T CM co-express CCR7 and CD45RO, having lost CD45RA during naïve → memory transition (32).…”

Section: Introductionmentioning

confidence: 99%

“…T EMRA lack both CCR7 and CD45RO and re-express CD45RA (34). A 4 th memory subset T SCM resides phenotypically within the naïve-like T-cell compartment (CD45RO − CD45RA + CCR7 + ), distinct from naïve T-cells by their expression of CD95 (Fas) (24, 31). Each T-cell subset has distinct engraftment capacities and function following adoptive transfer in preclinical trials (31–33, 35).…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive Approach for Identifying the T Cell Subset Origin of CD3 and CD28 Antibody–Activated Chimeric Antigen Receptor–Modified T Cells

Schmueck-Henneresse

Omer

Shum

et al. 2017

The Journal of Immunology

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The outcome of therapy with CAR-modified T-ells is strongly influenced by the subset origin of the infused T-cells. However, since polyclonally activated T-cells acquire a largely CD45RO+CCR7− effector memory phenotype after expansion, regardless of subset origin, it is impossible to know which subsets contribute to the final T-cell product. To determine the contribution of naïve (Tnaive), memory stem (TSCM), central memory (TCM), effector memory (TEM) and terminally differentiated effector (TEMRA) T-cell populations to the CD3 and CD28-activated CAR-T-cells that we use for therapy, we followed the fate and function of individually sorted CAR-T-cell subsets after activation with CD3 and CD28 antibodies (CD3/28), transduction and culture alone or after reconstitution into the relevant subset-depleted population. We show that all subsets are sensitive to CAR transduction and each developed a distinct T-cell functional profile during culture. Naïve-derived T-cells showed the greatest rate of proliferation but had more limited effector functions and reduced killing than memory-derived populations. When cultured in the presence of memory T-cells, naïve-derived T-cells show increased differentiation, reduced effector cytokine production, and a reduced re-proliferative response to CAR stimulation. CD3/28-activated T-cells expanded in IL-7 and IL-15 produced greater expansion of TSCM- and TCM-derived T-cells compared to IL-2. Our strategy provides a powerful tool to elucidate the characteristics of CAR T-cells, regardless of the protocol used for expansion, reveals the functional properties of each expanded T-cell subset and paves the way for a more detailed evaluation of the effects of manufacturing changes on the subset contribution to in vitro expanded T-cells.

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“…Petra Reinke also presented on a versatile expansion procedure for HCMV-specific T SCM using a pp65/IE1 overlapping peptide pool in the presence of IL-7 and IL-15. 22 Meanwhile, Ann Leen reported on beneficial effects of infusing T cell batches that recognize 12 immunogenic antigens related to five viruses (Epstein-Barr virus, adenovirus, HCMV, BKPyV and HHV-6) in allogeneic HSCT recipients. 23 Furthermore, she showed that "third party" virus-specific T cells can be infused in HSCT that have previously failed to respond to any conventional anti-viral therapy.…”

Section: Virus-specific T-cell Infusion As a Mainstream Antiviral Appmentioning

confidence: 98%

Infectious Diseases in Transplantation—Report of the 20th Nantes Actualités Transplantation Meeting

Haspot

Halary²

2015

Transplantation

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The 20th Nantes Actualités Transplantation (NAT) meeting was held on June 11, 2015, and June 12, 2015. This year, the local organizing committee selected an update on infectious diseases in solid organ and hematopoietic stem cell transplantation. With an attendance of close to 170 clinicians, researchers, students, engineers, technicians, invited speakers, and guests from North and South America, Germany, Switzerland, Netherlands, and France, the meeting was well attended. Invited speakers' expertise covered basic as well as translational microbiology, immunology, transplantation, and intensive care medicine. This report identifies a number of advances presented during the meeting in the care and management of infectious diseases in transplantation and immunocompromised patients. New antiviral immune responses and their modulation by pathogens in addition to novel antimicrobial therapeutic strategies, cell therapies, and genomic analysis were discussed.

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Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency

Cited by 34 publications

References 46 publications

Role of memory T cell subsets for adoptive immunotherapy

Role of memory T cell subsets for adoptive immunotherapy

Comprehensive Approach for Identifying the T Cell Subset Origin of CD3 and CD28 Antibody–Activated Chimeric Antigen Receptor–Modified T Cells

Infectious Diseases in Transplantation—Report of the 20th Nantes Actualités Transplantation Meeting

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