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Weissbrich B.,TU Munich | Nauerth M.,TU Munich | Busch D.H.,TU Munich | Busch D.H.,Helmholtz Center Munich | Busch D.H.,National Center for Infection Research
OncoImmunology | Year: 2013

T cells expressing high avidity T-cell receptors (TCRs) have been shown to mediate superior therapeutic effects. A novel koff-rate assay allows for the quantitative and reproducible assessment of the avidity of TCRs for their ligands directly on living T cells, ex vivo. This assay might facilitate the selection of T cells with an optimal avidity for their target, hence favoring the development of adoptive immunotherapeutic regimens. © 2013 Landes Bioscience. Source

Buchholz V.R.,TU Munich | Buchholz V.R.,Helmholtz Center Munich | Buchholz V.R.,National Center for Infection Research | Graf P.,TU Munich | Busch D.H.,TU Munich
Cellular and Molecular Life Sciences | Year: 2012

During the past two decades of research in T cell biology, an increasing number of distinct T cell subsets arising during the transition from naý̈ve to antigen-experienced T cells have been identified. Recently, it has been appreciated that, in different experimental settings, distinct T cell subsets can be generated in parallel within the same immune response. While signals driving a single ''lineage'' path of T cell differentiation are becoming increasingly clear, it remains largely enigmatic how the phenotypic and functional diversification creating a multi-faceted T cell response is achieved. Here, we review current literature indicating that diversification is a stable trait of CD8 + T cell responses. We showcase novel technologies providing deeper insights into the process of diversification among the descendants of individual T cells, and introduce two models that emphasize either intrinsic noise or extrinsic signals as driving forces behind the diversification of single cellderived T cell progeny populations in vivo. © 2011 Springer Basel AG. Source

Buchholz V.R.,TU Munich | Graf P.,TU Munich | Busch D.H.,TU Munich | Busch D.H.,Helmholtz Center Munich | Busch D.H.,National Center for Infection Research
Frontiers in Immunology | Year: 2013

CD8+ T cell immune responses provide immediate protection against primary infection and durable memory capable of rapidly fighting off re-infection. Immediate protection and lasting memory are implemented by phenotypically and functionally distinct T cell subsets. While it is now widely accepted that these diverge from a common source of naïve T cells (Tn), the developmental relation and succession of effector and memory T cell subsets is still under intense debate. Recently, a distinct memory T cell subset has been suggested to possess stem cell-like features, sparking the hope to harness its capacity for self-renewal and diversification for successful therapy of chronic infections or malignant diseases. In this review we highlight current developmental models of memory generation, T cell subset diversification and T cell stemness. We discuss the importance of single cell monitoring techniques for adequately mapping these developmental processes and take a brief look at signaling components active in the putative stem cell-like memory T cell compartment. © 2013 Buchholz, Gräf and Busch. Source

Dossinger G.,TU Munich | Bunse M.,Max Delbruck Center for Molecular Medicine | Bet J.,TU Munich | Albrecht J.,Helmholtz Center Munich | And 13 more authors.
PLoS ONE | Year: 2013

Adoptive therapy using T cells redirected to target tumor- or infection-associated antigens is a promising strategy that has curative potential and broad applicability. In order to accelerate the screening process for suitable antigen-specific T cell receptors (TCRs), we developed a new approach circumventing conventional in vitro expansion-based strategies. Direct isolation of paired full-length TCR sequences from non-expanded antigen-specific T cells was achieved by the establishment of a highly sensitive PCR-based T cell receptor single cell analysis method (TCR-SCAN). Using MHC multimer-labeled and single cell-sorted HCMV-specific T cells we demonstrate a high efficacy (approximately 25%) and target specificity of TCR-SCAN receptor identification. In combination with MHC-multimer based pre-enrichment steps, we were able to isolate TCRs specific for the oncogenes Her2/neu and WT1 even from very small populations (original precursor frequencies of down to 0.00005% of CD3+ T cells) without any cell culture step involved. Genetic re-expression of isolated receptors demonstrates their functionality and target specificity. We believe that this new strategy of TCR identification may provide broad access to specific TCRs for therapeutically relevant T cell epitopes. © 2013 Dössinger et al. Source

Busch D.H.,TU Munich | Busch D.H.,National Center for Infection Research | Frassle S.P.,TU Munich | Sommermeyer D.,Fred Hutchinson Cancer Research Center | And 5 more authors.
Seminars in Immunology | Year: 2016

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 its implications for adoptive immunotherapy. © 2016 Elsevier Ltd. Source

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