Interleukin-7 Is a Survival Factor for CD4+ CD25+ T-Cells and Is Expressed by Diabetes-Suppressive Dendritic Cells

Abstract

CD25؉ T-cells obtained from NOD-scid mice reconstituted with ex vivo engineered iDCs and NOD splenocytes expressed significantly higher levels of IL-7R␣ compared with levels in the CD4 ؉ CD25 ؊ subset, especially in diabetessuppressive dendritic cell-administered NOD-scid recipients. Taken together, our data suggest a novel mechanism by which iDCs delay autoimmunity through the CD4 ؉ CD25؉ Treg pathway and suggest IL-7 as a survival factor for these putative Tregs, which express the ␣-chain of its receptor at considerably higher levels than CD4 ؉ CD25 ؊ T-cells. Diabetes 55:158 -170, 2006

Study of the association between the CAPSL-IL7R locus and type 1 diabetes

“…This process is carried out in part through the enhancement of CD4 + CD25 + T regulatory cells. Both in vivo and in vitro experiments have demonstrated that IL7R is expressed at significantly higher levels on T regulatory cells than on CD4 + CD25 − cells [19]. Although these observations could explain the protective effect of the IL-7 and IL7R pathway, additional functional studies will be necessary to understand the underlying immunoregulatory mechanism.…”

Tolerance and Autoimmunity in Type 1 Diabetes

“…Mechanistically, functionally immature DCs, with low to absent costimulatory molecule expression, mediate peripheral tolerance by inducing T cell anergy and the expansion of antigen specific Foxp3 + CD25 + CD4 + Treg (Ueno et al, 2007). In our approach, AS-ODN DCs promote Treg cell survival through IL-7 signaling in addition to impaired provision of CD40, CD80 and CD86 costimulation (Harnaha et al, 2006). AS-ODN DCs, but not control DC, produce IL-7, in response to a secondary action of the antisense oligonucleotides on Toll Like Receptor (TLR) signaling.…”

Type 1 Diabetes Immunotherapy - Successes, Failures and Promises

“…NFkappaB decoys have been employed to prevent DC maturation preventing co-stimulatory molecule expression and reducing the incidence of diabetes development (Ma;Qian;Liang, et al, 2003). Administration of DC treated ex vivo with antisense oligonucleotides (AS-ODN) targeting the co-stimulatory molecules CD40, CD80, and CD86 similarly prevent diabetes development and could reverse new-onset diabetes in NOD mice Wright, et al, 2006, Machen;Lakomy, et al, 2004, Phillips, B.;Nylander;Harnaha, et al, 2008). The effects of the treatment extended beyond cyto-toxic T-cell hyporesponsiveness and include the augmentation of anti-inflammatory Treg Wright, et al, 2006, Machen;Lakomy, et al, 2004, Phillips, B.;Nylander;Harnaha, et al, 2008).…”

“…Administration of DC treated ex vivo with antisense oligonucleotides (AS-ODN) targeting the co-stimulatory molecules CD40, CD80, and CD86 similarly prevent diabetes development and could reverse new-onset diabetes in NOD mice Wright, et al, 2006, Machen;Lakomy, et al, 2004, Phillips, B.;Nylander;Harnaha, et al, 2008). The effects of the treatment extended beyond cyto-toxic T-cell hyporesponsiveness and include the augmentation of anti-inflammatory Treg Wright, et al, 2006, Machen;Lakomy, et al, 2004, Phillips, B.;Nylander;Harnaha, et al, 2008). Both methods are based on harvesting DC's from the mouse and then modifying ex vivo before being reintroduced back into the mouse.…”

“…In essence, co-stimulation deficient DC are phenotypically idnetical to immature DC which promote T-cell hyporesponsiveness and an overall state of tolerance. Stabilization of DC in an immature state has been a popular method of promoting auto-and allo-antigen tolerance in a variety of models (Beissert; Schwarz&Schwarz, 2006, Chen, 2006, Enk, 2006Wright, et al, 2006, Huber&Schramm, 2006Boissonnas;Amigorena, et al, 2006, Lohr;Knoechel&Abbas, 2006, Ma;Qian;Liang, et al, 2003, Machen;Lakomy, et al, 2004, Marguti;Yamamoto;da Costa, et al, 2009, Nouri-Shirazi&Thomson, 2006Nylander;Harnaha, et al, 2008, Roncarolo;Gregori;Battaglia, et al, 2006, Shevach;DiPaolo;Andersson, et al, 2006, Tang&Bluestone, 2006Olson, et al, 2004, Verhagen;Blaser;Akdis, et al, 2006, Yamazaki;Iyoda;Tarbell, et al, 2003, Zhang;Yi;Xia, et al, 2006). Recently, a phase I trial of AS-ODN treated DC's was completed in our center in established type 1 diabetic patients.…”