Low-affinity CD4+ T cells are major responders in the primary immune response

Martinez, Ryan; Andargachew, Rakieb; Martinez, Hunter A.; Evavold, Brian D.

doi:10.1038/ncomms13848

Cited by 62 publications

(74 citation statements)

References 77 publications

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“…Dimerization of pMHC via immune globulin fusion proteins can be sufficient to detect antigen‐specific T cells , but such pMHC dimers often fail to identify all antigen‐reactive T cells present in a polyclonal population . However, also pMHC tetramers might not label all epitope‐reactive T cells, which could be due to very low affinity TCRs or TCR/co‐receptor downregulation or variable surface distribution .…”

Section: Biological Applicationsmentioning

confidence: 99%

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

et al. 2019

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These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer‐reviewed by leading experts in the field, making this an essential research companion.

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Section: Biological Applicationsmentioning

confidence: 99%

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

et al. 2019

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“…In consequence, each TCR repertoire for a given foreign epitope most likely entails a precursor population with a spectrum of different affinities toward the epitope, thereby the majority of TCRs will be of low avidity. Indeed, positive selection by self‐peptides generates TCR repertoires very suitable for recognition of foreign epitopes, and first experimental data indicate that the naive TCR repertoire, beyond an avidity threshold, may entail many low avidity TCRs for a given epitope (Figure ). Several studies on the influence of TCR avidity on the composition of naive TCR repertoires have indicated an important role of TCR avidity toward self during thymic selection .…”

Section: Generation Of Naive Tcr Repertoiresmentioning

confidence: 99%

TCR repertoire evolution during maintenance of CMV‐specific T‐cell populations

Schober

Buchholz

Busch

2018

Immunological Reviews

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During infections and cancer, the composition of the T-cell receptor (TCR) repertoire of antigen-specific CD8 T cells changes over time. TCR avidity is thought to be a major driver of this process, thereby interacting with several additional regulators of T-cell responses to form a composite immune response architecture. Infections with latent viruses, such as cytomegalovirus (CMV), can lead to large T-cell responses characterized by an oligoclonal TCR repertoire. Here, we review the current status of experimental studies and theoretical models of TCR repertoire evolution during CMV infection. We will particularly discuss the degree to which this process may be determined through structural TCR avidity. As engineered TCR-redirected T cells have moved into the spotlight for providing more effective immunotherapies, it is essential to understand how the key features of a given TCR influence T-cell expansion and maintenance in settings of infection or malignancy. Deeper insights into these mechanisms will improve our basic understanding of T-cell immunology and help to identify optimal TCRs for immunotherapy.

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“…The expansion of high affinity, MOG tetramer positive T cells are a relatively small population within the polyclonal repertoire (25-27, 63) and expansion or engraftment numbers has been associated with spontaneous EAE in retrogenic models (49). While NFM can expand a limited number of MOG tetramer positive T cells, these cells are not able to migrate to the CNS and cause EAE.…”

Section: Discussionmentioning

confidence: 99%

NFM Cross-Reactivity to MOG Does Not Expand a Critical Threshold Level of High-Affinity T Cells Necessary for Onset of Demyelinating Disease

Blanchfield

Sabatino

Lawrence

et al. 2017

The Journal of Immunology

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Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4+ T cells due to cross-recognition of multiple self-epitopes such as has been suggested for MOG35-55 and NFM15-35. NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic antigen. Despite reported cross-reactivity with MOG specific T cells, the polyclonal response to NFM15-35 did not expand threshold numbers of MOG38-49 tetramer positive T cells. Furthermore, NFM lacked functional synergy with MOG to promote EAE because NFM-/- mice developed an identical disease course to wild type mice after challenge with MOG35-55. Single cells analysis of encephalitogenic T cells using the pMHC monomer based 2D micropipette adhesion frequency assay confirmed that NFM was not a critical antigen driving demyelinating disease because NFM18-30 specific T cells in the CNS were predominantly reactive to MOG38-49. The absence of NFM contribution to disease allowed mapping of the amino acids required for encephalitogenicity and expansion of high affinity, MOG specific T cells that defined the polyclonal response. Alterations of N-terminal residues outside of the NFM15-35 core nonamer promoted expansion of high affinity, MOG38-49 tetramer positive T cells and promoted consistent EAE induction, unlike mice challenged with NFM15-35. While NFM15-35 is immunogenic and cross-reactive with MOG at the polyclonal level, it fails to expand a threshold level of encephalitogenic, high affinity MOG specific T cells.

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Low-affinity CD4+ T cells are major responders in the primary immune response

Cited by 62 publications

References 77 publications

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

TCR repertoire evolution during maintenance of CMV‐specific T‐cell populations

NFM Cross-Reactivity to MOG Does Not Expand a Critical Threshold Level of High-Affinity T Cells Necessary for Onset of Demyelinating Disease

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