TCR affinity and specificity requirements for human regulatory T-cell function

Plesa, Gabriela; Zheng, Lingjie; Medvec, Andrew; Wilson, Caleph B.; Robles-Oteiza, Camila; Liddy, Nathaniel; Bennett, Alan; Gavarret, Jessie; Vuidepot, Annelise; Zhao, Yangbing; Blazar, Bruce R.; Jakobsen, Bent K.; Riley, James L.

doi:10.1182/blood-2011-09-377051

Cited by 48 publications

(43 citation statements)

References 48 publications

(69 reference statements)

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“…16,17 Recently, the generation of antigenspecific human Tregs via viral transduction of a tumor-associated antigen-specific TCR was reported. 9,11,18 These results indicated that transduction of specific TCR could render Tregs antigen specific (monoclonal) and able to suppress immune responses to specific antigens. In these earlier studies, however, functional stability of the Tregs was not clearly addressed.…”

Section: Introductionmentioning

confidence: 91%

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

Kim

Zhang

et al. 2015

Blood

136

154

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Expansion of human regulatory T cells (Tregs) for clinical applications offers great promise for the treatment of undesirable immune responses in autoimmunity, transplantation, allergy, and antidrug antibody responses, including inhibitor responses in hemophilia A patients. However, polyclonal Tregs are nonspecific and therefore could potentially cause global immunosuppression. To avoid this undesirable outcome, the generation of antigen-specific Tregs would be advantageous. Herein, we report the production and properties of engineered antigen-specific Tregs, created by transduction of a recombinant T-cell receptor obtained from a hemophilia A subject's T-cell clone, into expanded human FoxP3(+) Tregs. Such engineered factor VIII (FVIII)-specific Tregs efficiently suppressed the proliferation and cytokine production of FVIII-specific T-effector cells. Moreover, studies with an HLA-transgenic, FVIII-deficient mouse model demonstrated that antibody production from FVIII-primed spleen cells in vitro were profoundly inhibited in the presence of these FVIII-specific Tregs, suggesting potential utility to treat anti-FVIII inhibitory antibody formation in hemophilia A patients.

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Section: Introductionmentioning

confidence: 91%

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

Kim

Zhang

et al. 2015

Blood

136

154

View full text Add to dashboard Cite

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“…This result suggests that LYP-mediated dampening of TCR activation preferentially impairs effector T cells and tilts the balance toward regulation. It has been reported that Tregs can be activated to suppress by low affinity ligands whereas activation of effector function in Tconv cells requires higher affinity engagement with antigens [50]. Strikingly, the differential requirement can be three orders in magnitude.…”

Section: Ptpn22mentioning

confidence: 86%

Restoring Regulatory T Cells in Type 1 Diabetes

Spence

Tang

2016

Curr Diab Rep

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“…antigen[specific) suppression) in) Tregs) transfected) with) a) high) affinity) HIV[ specific)TCR)and)a)lower)affinity)tumor)antigen[specific)TCR [22]. )However,)it) should) be) noted) that) the) study) was) performed) using) MHC) class) I[restricted)…”

Section: 6# Data#analysis# )unclassified

Generation of human islet-specific regulatory T cells by TCR gene transfer

Hull

Nickolay

Estorninho

et al. 2017

Journal of Autoimmunity

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107

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! 1! Generation) of) human) islet0specific) regulatory) T) cells) by) TCR) gene) transfer.) )Caroline)M.)Hull 1,5) *,)Lauren)E.)Nickolay 1,5 ,)Megan)Estorninho 1,5 ,)Max)W.) Richardson 2 ,)James)L.)Riley 2 ,)Mark)Peakman 1,3,4,5 ,)John)Maher 5,6,7 ,)Timothy) I.M.)Tree 1,5) *) ) 1 Department)of)Immunobiology,)Faculty)of)Life)Sciences)&)Medicine,)King's) College)London,)London)SE1)9RT,)UK) ) 2 Department)of)Microbiology,)University)of)Pennsylvania)School)of)Medicine,) Philadelphia,)Pennsylvania,)USA) ) 3 Peak)Therapeutics,)London)SE24)9LG,)UK ) 4 Division)of)Diabetes)and)Nutrition,)King's)College)London)SE1)1UL,)UK) ) 5 NIHR)Biomedical)Research)Centre,)Guy's)and)St)Thomas')NHS)Foundation) Trust)and)King's)College)London,)London)SE1)9RT,)UK) ) 6) CAR)Mechanics)Group,)Division)of)Cancer)Studies,)Guy's)Hospital)Campus,) King's)College)London)School)of)Medicine,)London)SE1)1UL,)UK) ) 7 Department)of)Allergy)and)Immunology,)King's)College)Hospital)National) Health)Service)Foundation)Trust,)London)SE5)9RS,)UK) ) ) Short)Running)Title:)Generation)of)human)islet[specific)Tregs.) ) ) ) *Corresponding)authors) ) caroline.hull@kcl.ac.uk) timothy.tree@kcl.ac.uk) ) ! 2! Abstract) )Based)on)the)success)in)animal)models)of)type)1)diabetes)(T1D),)clinical)trials) of) adoptive) regulatory) T) cell) (Treg)) therapy) are) underway) using) ex# vivo) expanded)polyclonal)Tregs.)However,)pre[clinical)data)also)demonstrate)that)islet[specific) Tregs) are) more) potent) than) polyclonal) Tregs) at) reversing) T1D.)Translation) of) this) approach) into) man) will) require) methods) to) generate) large) populations) of) islet[specific) Tregs) which,) to) date,) has) proved) to) be) a) major)hurdle.)Here)we)demonstrate)the)feasibility)of)lentiviral[mediated)T)cell)receptor) (TCR))gene)transfer)to)confer)antigen)specificity)on)polyclonal)human)Tregs.)Targeting) has) been) achieved) using) TCRs) isolated) from) human) islet [specific) and) viral[specific) CD4+) T) cell) clones.) Engineered) T) cells) demonstrated) expression)of)ectopically[delivered)TCRs,)resulting)in)endowment)of)cognate)antigen[specific) responses.) This) enabled) antigen[specific) suppression) at) increased)potency)compared)to)polyclonal)Tregs.)However,)cells)transduced) with) islet[specific) TCRs) were) less) responsive) to) cognate) antigen) than) viral[ specific) TCRs,) and) in) some) cases,) required) additional) methods) to) isolate) functional)antigen[specific)Tregs.)This)study)demonstrates)the)potential)of)TCR) gene)transfer)to)develop)islet[specific)Treg)therapies)for)effective)treatment)of) T1D,)but)also)highlights)that)additional)optimisation)may)be)required)to)achieve)Populations) of) Tregs) found) in) the) periphery,) including) those) expressing) the)with)T1D.)This)abnormality)is)evident)before)clinical)diagnosis,)at)the)time)of) diagnosis) and) many) years) following) onset) of) T1D [4[7].) Since) defective) Treg) function) appears) to) be) central) to) the) pathogenesis) of) T1D,) it) is) logical) to) hypothesise) that) correction) of) this) imbalance) may...

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TCR affinity and specificity requirements for human regulatory T-cell function

Cited by 48 publications

References 48 publications

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

Engineered antigen-specific human regulatory T cells: immunosuppression of FVIII-specific T- and B-cell responses

Restoring Regulatory T Cells in Type 1 Diabetes

Generation of human islet-specific regulatory T cells by TCR gene transfer

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