Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice

Degauque, Nicolas; Mariat, Christophe; Kenny, James J.; Zhang, Dong; Gao, Wenda; Vu, Minh Diem; Alexopoulos, Sophoclis P.; Oukka, Mohammed; Umetsu, Dale T.; DeKruyff, Rosemarie H.; Kuchroo, Vijay K.; Zheng, Xin Xiao; Strom, Terry B.

doi:10.1172/jci32562

Cited by 111 publications

(111 citation statements)

References 39 publications

Supporting

Mentioning

106

Contrasting

Order By: Relevance

“…In addition, Kasprowicz et al showed FoxP3 down-regulation and secretion of IFN-g and IL-4 by FoxP3-transgenic T cells after culturing the cells under Th1 or Th2 driving conditions, respectively [27]. Importantly, Degauque et al and Vu et al both reported similar effects, either after treatment of natural Treg with an agonistic antibody to Tim-1 [28], or by triggering them via the OX40 receptor [29], indicating that a deprogramming of Treg can also occur after their interaction with physiological ligands. We now confirm this developmental flexibility in human natural Treg and demonstrate for the first time that loss of FOXP3 expression in these cells occurs even in the absence of a pro-inflammatory milieu, but solely upon repetitive polyclonal TCR and CD28 co-receptor-mediated stimulation.…”

Section: Discussionmentioning

confidence: 94%

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

View full text Add to dashboard Cite

The adoptive transfer of CD4 1 CD25 1 natural regulatory T cells (Treg) is a promising strategy for the treatment of autoimmune diseases and the prevention of alloresponses after transplantation. Clinical trials exploring this strategy require efficient in vitro expansion of this rare cell population. Protocols developed thus far rely on high-grade purification of Treg prior to culture initiation, a process still hampered by the lack of Treg cell-specific surface markers. Depletion of CD127 1 cells was shown to separate activated conventional T cells from natural Treg cell populations allowing the isolation of highly enriched FOXP3 1 cells with all functional and molecular characteristics of natural Treg. Here, we demonstrate that upon in vitro expansion, CpG methylation in a conserved region within the FOXP3 gene locus increased in CD4 1 CD25 1 CD127 low Treg, correlating with loss of FOXP3 expression and emergence of pro-inflammatory cytokines. Further analysis identified CD45RA À FOXP3 1 memory-type Treg as the main source of converting cells, whereas CD45RA 1 FOXP3 1 Treg from the same donors showed no conversion within 3 wk of in vitro expansion. Thus, Treg cell lineage differentiation does not seem to represent a final fate decision, as natural Treg can lose their cell-type-specific characteristics after repetitive TCR stimulation.Key words: Cellular therapy . Immune regulation . Treg Supporting Information available online Introduction CD4 1 CD25 1 Treg are pivotal for the maintenance of peripheral self-tolerance and imbalances in this T-cell compartment have been shown to contribute to various autoimmune diseases [1]. In murine disease models, adoptively transferred Treg prevent, and in some cases, even cure autoimmunity [2,3]. In addition, they protect from graft rejection after allogeneic organ transplantation [4] as well as from graft-versus-host disease after MHCmismatched stem cell transplantation [5][6][7][8]. Recently, a limited number of Phase I clinical trials exploring the adoptive transfer of Treg have been initiated and several additional trials in various clinical settings are in preparation [9,10]. Prerequisites for the initiation of such trials are (i) the availability of efficient in vitro expansion protocols for this rare cell population and (ii) the ability to unequivocally identify Treg to avoid contamination of 1088Treg cultures with potentially harmful conventional effector T cells (Tconv). While efficient cell culture protocols have recently been established by us and others for the polyclonal as well as antigen-specific Treg cell expansion [11][12][13], the search for an exclusive surface marker for Treg is still ongoing.Contrary to earlier reports, human CD4 1 CD25 high Treg in adult peripheral blood have recently been shown to comprise not only (self-)antigen-experienced, CD45RA À central and effector memory cells, but also a subpopulation of CD45RA 1 naïve recent thymic emigrants [14,15]. We previously demonstrated that these CD45RA 1 CD4 1 CD25 high T cells (RA 1 Treg) homogen...

show abstract

Section: Discussionmentioning

confidence: 94%

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Cross-linking of Tim-1 on the surface of T cells in vitro by Tim-4Ig enhanced T cell proliferation, and production of Th1 and Th2 cytokines and in vivo administration of Tim-4Ig during an ongoing immune response created similar effects (23). Tim-1:Tim-4 signaling also greatly enhances proinflammatory T17 responses (15). Using an antagonistic Tim-1-specific mAb (RMT1-10), we recently reported the role of Tim-1 in alloimmunity (16).…”

Section: Discussionmentioning

confidence: 97%

“…2B and 3C), indicating that CD8 T17 cells in particular are resistant to CTLA4IgϩMR1, and other pathways and mechanisms are operative in maintaining T17 immune responses. Two such pathways are the ICOS-ICOSL pathway and the costimulatory Tim-1:Tim-4 pathway (14)(15)(16)18). Naïve CD4 T cells up-regulate Tim-1 expression early after activation, and Tim-1 cell-surface expression is maintained through differentiation into the Th1 or Th2 phenotype, with higher expression on Th2 cells (36).…”

Section: Discussionmentioning

confidence: 99%

“…Our in vivo data are in keeping with previous in vitro studies linking Tim-1 signaling with Th2/T17 immunity and indicates that Tim-1:Tim-4 pathway plays a critical role in regulating alloreactive T17 responses. Further, Tim-1:Tim-4 signaling, in addition to greatly enhancing proinflammatory Th1 and T17 responses, limits the generation and functional capacity of Tregs (15). However until recently, Tim-1 signaling was thought to be primarily important in CD4 T cell co-stimulation, but a recent study noted that CD8 T cell proliferation was also enhanced by agonistic anti-Tim-1 mAb (15).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

Yuan

Ansari

D’Addio

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The ability to induce durable transplantation tolerance predictably and consistently in the clinic is a highly desired but elusive goal. Progress is hampered by lack of appropriate experimental models in which to study resistance to transplantation tolerance. Here, we demonstrate that T helper 1-associated T box 21 transcription factor (Tbet) KO recipients exhibit allograft tolerance resistance specifically mediated by IL-17-producing CD8 T (T17) cells. Neutralization of IL-17 facilitates long-term cardiac allograft survival with combined T cell co-stimulation (CD28-CD80/86 and CD154-CD40) blockade in Tbet KO recipients. We have used this T17-biased Tbet KO model of allograft tolerance resistance to study the impact of targeting a T cell-costimulatory pathway, and demonstrate that targeting T cell Ig and mucin domain-1 (Tim-1) with anti-Tim-1 overcomes this resistance by specifically inhibiting the pathogenic IL-17-producing CD8 T17 cells. These data indicate that in the absence of Th1 immunity, CD8 T17 alloreactivity constitutes a barrier to transplantation tolerance. Targeting TIM-1 provides an approach to overcome resistance to tolerance in clinical transplantation.costimulation ͉ IL-17 ͉ rejection ͉ immunosuppression

show abstract

“…Anti‐TIM‐1 antibody (Clone RMT1‐10) ameliorates Experimental autoimmune encephalomyelitis (EAE),17 allergic asthma,37 glomerulonephritis38 and corneal allograft rejection 39. In contrast another anti‐TIM‐1 antibody (clone 3B3) enhances T cell proliferation and Th2 effector function 17, 40, 41. HFD‐fed LDLR‐deficient mice treated with anti‐TIM‐1 antibody (clone 3D10) accelerated atherosclerosis by ≈50% via increased aortic CD4 T cells 42.…”

Section: Discussionmentioning

confidence: 99%

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Hosseini

Kanellakis

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundPeritoneal B1a cells attenuate atherosclerosis by secreting natural polyclonal immunoglobulin M (IgM). Regulatory B cells expressing T‐cell immunoglobulin mucin domain‐1 (TIM‐1) expanded through TIM‐1 ligation by anti‐TIM‐1 monoclonal antibody (RMT1‐10) induces immune tolerance.Methods and ResultsWe examined the capacity of RMT1‐10 to expand peritoneal B1a cells to prevent atherosclerosis development and retard progression of established atherosclerosis. RMT1‐10 treatment selectively doubled peritoneal B1a cells, tripled TIM‐1+ B1a cells and increased TIM‐1+IgM+interleukin (IL)‐10+ by 3‐fold and TIM‐1+IgM+IL‐10− B1a cells by 2.5‐fold. Similar expansion of B1a B cells was observed in spleens. These effects reduced atherosclerotic lesion size, increased plasma IgM and lesion IgM deposits, and decreased oxidatively modified low‐density lipoproteins in lesions. Lesion CD4+ and CD8+ T cells, macrophages and monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, expression of proinflammatory cytokines monocyte chemoattractant protein‐1, vascular cell adhesion molecule‐1, IL1β, apoptotic cell numbers and necrotic cores were also reduced. RMT1‐10 treatment failed to expand peritoneal B1a cells and reduce atherosclerosis after splenectomy that reduces B1a cells, indicating that these effects are B1a cell‐dependent. Apolipoprotein E‐KO mice fed a high‐fat diet for 6 weeks before treatment with RMT1‐10 also increased TIM‐1+IgM+ IL‐10+ and TIM‐1+IgM+ IL‐10− B1a cells and IgM levels and attenuated progression of established atherosclerosis.Conclusions RMT1‐10 treatment attenuates atherosclerosis development and progression by selectively expanding IgM producing atheroprotective B1a cells. Antibody‐based in vivo expansion of B1a cells could be an attractive approach for treating atherosclerosis.

show abstract

Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice

Cited by 111 publications

References 39 publications

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Contact Info

Product

Resources

About

Immunostimulatory Tim-1–specific antibody deprograms Tregs and prevents transplant tolerance in mice

Cited by 111 publications

References 39 publications

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4+CD25+ regulatory T cells upon repetitive in vitro stimulation

Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells

Anti‐TIM‐1 Monoclonal Antibody (RMT1‐10) Attenuates Atherosclerosis By Expanding IgM‐producing B1a Cells

Contact Info

Product

Resources

About

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation

Loss of FOXP3 expression in natural human CD4⁺CD25⁺ regulatory T cells upon repetitive in vitro stimulation