In vivo expansion of T reg cells with IL-2–mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression

Self Cite

319

340

IL-2 immunotherapy is an attractive treatment option for certain metastatic cancers. However, administration of IL-2 to patients can lead, by ill-defined mechanisms, to toxic adverse effects including severe pulmonary edema. Here, we show that IL-2–induced pulmonary edema is caused by direct interaction of IL-2 with functional IL-2 receptors (IL-2R) on lung endothelial cells in vivo. Treatment of mice with high-dose IL-2 led to efficient expansion of effector immune cells expressing high levels of IL-2Rβγ, including CD8 + T cells and natural killer cells, which resulted in a considerable antitumor response against s.c. and pulmonary B16 melanoma nodules. However, high-dose IL-2 treatment also affected immune cell lineage marker-negative CD31 + pulmonary endothelial cells via binding to functional αβγ IL-2Rs, expressed at low to intermediate levels on these cells, thus causing pulmonary edema. Notably, IL-2–mediated pulmonary edema was abrogated by a blocking antibody to IL-2Rα (CD25), genetic disruption of CD25, or the use of IL-2Rβγ–directed IL-2/anti-IL-2 antibody complexes, thereby interfering with IL-2 binding to IL-2Rαβγ + pulmonary endothelial cells. Moreover, IL-2/anti-IL-2 antibody complexes led to vigorous activation of IL-2Rβγ + effector immune cells, which generated a dramatic antitumor response. Thus, IL-2/anti-IL-2 antibody complexes might improve current strategies of IL-2–based tumor immunotherapy.

Section: Discussionmentioning

confidence: 99%

“…Notably, IL-2-mediated pulmonary edema was not an issue when Treg numbers were raised after a brief course of IL-2/mAb CD25 injections or with low doses of IL-2/mAb CD25 treatment. These latter approaches might be useful for the treatment of allergies, autoimmune disease, and allograft rejection (11,28,30).…”

Section: Discussionmentioning

confidence: 99%

Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

Krieg

Létourneau

Pantaleo

et al. 2010

Self Cite

319

340

“…1C Lower). The combination of antigen plus everolimus injection followed by injection of IL-2/IL-2 antibody complexes clearly represented the most powerful means of increasing Treg numbers, but as earlier demonstrated (20), the expanded proportion and absolute number of Tregs were not stable over prolonged time periods. Thus in contrast to the conversion enhanced by everolimus, which resulted in a nearly stable high proportion of converted Tregs up to several weeks after conversion (Fig.…”

Section: Resultsmentioning

confidence: 83%

“…IL-2/IL-2ab complexes IL-2/IL2ab complexes do not only expand naturally generated Treg in vivo as described (20) but can also be used to expand recently in vivo converted Tregs. It was noted, however, that the injection of IL-2/ IL-2 complexes IL-2/IL-2ab complexes resulted not only in the expansion of Foxp3 + Tregs but also increased numbers of Foxp3 − , CD25 + cells.…”

Section: Resultsmentioning

confidence: 99%

Enhancement of antigen-specific Treg vaccination in vivo

Daniel

Wennhold²,

Kim³

et al. 2010

The conversion of naive T cells into Treg can be achieved in vivo by delivery of antigen under subimmunogenic conditions. Here we have examined several drugs for their ability to enhance the conversion process in vivo and have found that the rapamycin analog everolimus potently enhances Treg conversion by interfering with T-cell costimulation, reducing cell division and thereby activation of DNA methyltransferase 1 as well as by reducing T-cell activation through the ATP-gated P2×7 receptor controlling Ca2 + influx. The resulting Tregs exhibit increased stability of Foxp3 expression even when generated in TGFβ-containing media in vitro. Thus the mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to inhibiting immune responses enhances Treg conversion by several distinct pathways. The converted Tregs can be further expanded by injection of IL-2/IL-2ab complexes. These complexes also increase the number of CD25 + Foxp3 − cells that, however, do not represent cytokine secreting effector cells but anergic cells, some of which can secrete IL-10 and can themselves be considered regulatory T cells as well. The combined use of everolimus and IL-2/IL-2ab complexes in vivo makes it feasible to achieve highly effective antigen-driven conversion of naive T cells into Treg and their expansion in vivo and thereby the described protocols constitute important tools to achieve immunological tolerance by Treg vaccination.antigen-specific Treg conversion | Foxp3 | IL-2/IL-2ab complexes | mammalian target of rapamycin | prospective tolerance A t present it is unclear how much the conversion of naive T cells into Treg in peripheral lymphoid tissue contributes to the control of immunity by Treg. On the other hand, it seems reasonable to exploit this conversion process to control unwanted immune responses. In the past our lab has described several strategies to induce such conversion by exogenous antigens with the aim to study whether Treg conversion can be used to induce tolerance to antigens, including transplantation antigens, prospectively (1-3). We were successful in using this approach to induce prospective tolerance in female mice to a variety of male tissues, including skin and hematopoetic grafts (4).With regard to mechanisms it became clear that Treg conversion in vivo is best achieved by subimmunogenic delivery of strong agonists under conditions that avoid functional activation of antigen presenting cells (5-9). Also, in accordance with more recent data (10), in this setting, best conversion is seen in T cells that undergo only limited proliferation, whereas higher doses of the strong agonist result in more extensive proliferation and diminished conversion (5). Thus these studies that addressed Treg conversion by monitoring the generation of Foxp3-expressing Treg in vivo confirmed anecdotal evidence of generating "dominant" tolerance by subimmunogenic antigen delivery (10).Comparison of such converted Treg with Treg generated by T-cell stimulation in vitro in the presence of relatively high doses of tran...

“…To address the effect of adding IL-2, we used IL-2/anti-IL-2 complexes that have been demonstrated to expand Treg cells efficiently in vivo (33). Because the spleen contained a relatively large proportion of CD25 − Tfr cells (Fig.…”

Section: Il-2 Antagonizes the Formation And Maintenance Of Cd25 − Tfrmentioning

confidence: 99%

A distinct subpopulation of CD25⁻T-follicular regulatory cells localizes in the germinal centers

Wing

Kitagawa

Locci

et al. 2017

171

236

T-follicular helper (Tfh) cells differentiate through a multistep process, culminating in germinal center (GC) localized GC-Tfh cells that provide support to GC-B cells. T-follicular regulatory (Tfr) cells have critical roles in the control of Tfh cells and GC formation. Although Tfh-cell differentiation is inhibited by IL-2, regulatory T (Treg) cell differentiation and survival depend on it. Here, we describe a CD25− subpopulation within both murine and human PD1+CXCR5+Foxp3+ Tfr cells. It is preferentially located in the GC and can be clearly differentiated from CD25+ non–GC-Tfr, Tfh, and effector Treg (eTreg) cells by the expression of a wide range of molecules. In comparison to CD25+ Tfr and eTreg cells, CD25− Tfr cells partially down-regulate IL-2–dependent canonical Treg features, but retain suppressive function, while simultaneously up-regulating genes associated with Tfh and GC-Tfh cells. We suggest that, similar to Tfh cells, Tfr cells follow a differentiation pathway generating a mature GC-localized subpopulation, CD25− Tfr cells.