Differential effects of IL-2 and IL-21 on expansion of the CD4+CD25+Foxp3+ T regulatory cells with redundant roles in natural killer cell mediated antibody dependent cellular cytotoxicity in chronic lymphocytic leukemia

Aruna Gowda,Asha Ramanunni,Carolyn Cheney,Darlene Rozewski,Wayne Kindsvogel,Amy Lehman,David Jarjoura,Michael Caligiuri,John C Byrd,Natarajan Muthusamy

doi:10.4161/mabs.2.1.10561

Aruna Gowda, Asha Ramanunni + Show 8 more

Open Access

https://doi.org/10.4161/mabs.2.1.10561

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Journal: mAbs	Publication Date: Jan 1, 2010
Citations: 26	License type: cc-by

Affiliation: The Ohio State University

Abstract

CD4+ CD25+ regulatory T cells are expanded in solid and hematological malignancies including Chronic Lymphocytic Leukemia (CLL). Several cytokines and co-stimulatory molecules are required for generation, survival and maintenance of their suppressive effect. We and others have shown direct cytotoxic effect of the novel common gamma chain cytokine interleukin- 21 (IL-21) on primary B cells from CLL patients. Since members of this family of cytokines are known to exhibit their effects on diverse immune cells, we have examined the effects of IL-21 on CLL patient derived regulatory T cell induction, expansion and the inhibitory effect on natural killer cells in vitro. We demonstrate here the expression of IL-21 receptor in CD4+CD25High regulatory cells from CLL patients. In contrast to IL-2, the IL-21 cytokine failed to mediate expansion of regulatory T cells or induced expression of Foxp3 in CD4+CD25Intermediate or CD4+CD25Dim/- T cells in whole blood derived from CLL patients. Interestingly, in contrast to their differential effects on expansion of the CD4+CD25+Foxp3+T cells, IL-2 and IL-21 exhibited a redundant role in T-reg mediated suppression of NK cell mediated antibody dependent cytotoxicity function. Given the infusion related toxicities and pro-survival effect of IL-2 in CLL, these studies provide a rationale to explore IL-21 as an alternate gamma chain cytokine in CLL therapy.

Highlights

T regulatory cells (Tregs) are CD4+CD25High T cells identified by their expression of forkhead transcription factor (Foxp3).[1]
While common gamma chain cytokines such as IL-2 and IL-21 have been shown to exert diverse effects on multiple cell types including B cells, T cells and natural killer cell (NK) cells, little is known of their effect on CD4+CD25High Tregs from chronic lymphocytic leukemia (CLL) patients
As the IL-21 receptor expression has been observed in B cells and CD4+ T cells, we first examined whether the CD4+CD25+ Treg cells isolated from CLL patients express IL-21 receptor

Summary

Introduction

T regulatory cells (Tregs) are CD4+CD25High T cells identified by their expression of forkhead transcription factor (Foxp3).[1]. Tregs exhibit immuneregulatory properties and their dysfunction has been implicated in the development of allergic and autoimmune diseases.[2] The increased numbers of Tregs are observed in several malignancies and have been implicated in additional mechanisms reducing immunity, which may contribute to poor prognosis and responses to chemotherapy.[3,4] The number and inhibitory functions of the Tregs can be decreased by chemotherapeutic agents such as fludarabine therapy in chronic lymphocytic leukemia (CLL).[5] Tregs can develop both in the thymus and periphery. Tregs that develop in the thymus are called natural Tregs (nTregs) and those that are actively generated in the periphery through the conversion of CD4+CD25- T cells into Foxp3+ cells are known as induced Tregs.[6] increased Tregs is a characteristic feature in many tumors, the molecular and cellular basis for their increase and maintenance is not clearly understood.[3]

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