Type 1 diabetes is an autoimmune disease characterised by the destruction of insulin producing beta cells in the pancreas. Whilst it remains unclear what the original triggering factors for this destruction are, observations from the natural history of human type 1 diabetes, including incidence rates in twins, suggest that the disease results from a combination of genetic and environmental factors. Whilst many different immune cells have been implicated, including members of the innate and adaptive immune systems, a view has emerged over the past 10 years that beta cell damage is mediated by the combined actions of CD4 + and CD8 + T cells with specificity for islet autoantigens. In health, these potentially pathogenic T cells are held in check by multiple regulatory mechanisms, known collectively as 'immunological tolerance'. This raises the question as to whether type 1 diabetes develops, at least in part, as a result of a defect in one or more of these control mechanisms. Immunological tolerance includes both central mechanisms (purging of the T cell repertoire of high-affinity autoreactive T cells in the thymus) and peripheral mechanisms, a major component of which is the action of a specialised subpopulation of T cells, known as regulatory T cells (Tregs). In this review, we highlight the evidence suggesting that a reduction in the functional capacity of different Treg populations contributes to disease development in type 1 diabetes. We also address current controversies regarding the putative causes of this defect and discuss strategies to correct it as a means to reduce or prevent islet destruction in a clinical setting.
! 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...
T-cell depletion therapy is used to prevent acute allograft rejection, treat autoimmunity and create space for bone marrow or hematopoietic cell transplantation. The evolved response to T-cell loss is a transient increase in IL-7 that drives compensatory homeostatic proliferation (HP) of mature T cells. Paradoxically, the exaggerated form of this process that occurs following lymphodepletion expands effector T-cells, often causing loss of immunological tolerance that results in rapid graft rejection, autoimmunity, and exacerbated graft-versus-host disease (GVHD). While standard immune suppression is unable to treat these pathologies, growing evidence suggests that manipulating the incipient process of HP increases allograft survival, prevents autoimmunity, and markedly reduces GVHD. Multipotent adult progenitor cells (MAPC) are a clinical grade immunomodulatory cell therapy known to alter γ-chain cytokine responses in T-cells. Herein, we demonstrate that MAPC regulate HP of human T-cells, prevent the expansion of Th1, Th17, and Th22 effectors, and block the development of pathogenic allograft responses. This occurs via IL-1β-primed secretion of PGE2 and activates T-cell intrinsic regulatory mechanisms (SOCS2, GADD45A). These data provide proof-of-principle that HP of human T-cells can be targeted by cellular and molecular therapies and lays a basis for the development of novel strategies to prevent immunopathology in lymphodepleted patients.
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