Expression and function of the TL1A/DR3 axis in chronic lymphocytic leukemia.

Chiara Cavallini,Giorgio Malpeli,Maria Teresa Scupoli,Fiorenza Aprili,Elda Mimiola,Ornella Lovato,Elisa Zoratti,Martina Tinelli,Marco Antonio Cassatella,Giovanni Pizzolo,Omar Perbellini,Cristina Tecchio,Aldo Scarpa,Anna Bertolaso,Alberto Zamò

doi:10.18632/oncotarget.5201

Chiara Cavallini, Giorgio Malpeli + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.5201

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Abstract

TNF-like ligand 1A (TL1A) and its unique receptor death receptor 3 (DR3) acts as broad T-cell costimulator involved in regulatory mechanisms of adaptive immune response under physiological and pathological settings. Moreover, we have recently shown that TL1A negatively regulates B-cell proliferation. Despite increasing interest on the TL1A/DR3-axis functions, very little is known on its expression and role in leukemia. In this study, we investigated the expression and function of TL1A/DR3 axis in chronic lymphocytic leukemia (CLL). DR3 was differentially expressed in activated CLL cells and predominantly detected in patients with early clinical stage disease. Soluble TL1A has been revealed in the sera of CLL patients where higher TL1A levels were associated with early stage disease. T cells, monocytes and leukemic B cells have been identified as major sources of TL1A in CLL. The relevance of these findings has been sustained by functional data showing that exogenous TL1A reduces CLL proliferation induced by stimulation of the B cell receptor. Overall, these data document the expression of the TL1A/DR3 axis in early-stage CLL. They also identify a novel function for TL1A as a negative regulator of leukemic cell proliferation that may influence the CLL physiopathology and clinical outcome at an early-stage disease.

Highlights

Death receptor 3 (DR3/TNFRSF25) is a member of the TNFR superfamily that contains a death domain (DD) as part of its intracellular domain [1,2,3]
This study documents that the TNF-like ligand 1A (TL1A)/death receptor 3 (DR3) molecular system is expressed in chronic lymphocytic leukemia (CLL) and functions as a negative regulator of leukemic cell proliferation
This study assesses the association between TL1A/DR3 expression and early stage disease and points out the importance of the TL1A/ DR3 axis in the physiopathology of CLL

Summary

Introduction

Death receptor 3 (DR3/TNFRSF25) is a member of the TNFR superfamily that contains a death domain (DD) as part of its intracellular domain [1,2,3]. DR3 expression is restricted to lymphocyte-enriched tissues, including peripheral blood leukocytes, thymus and spleen [4] It is especially upregulated in activated T cells [4, 5]. Ligation of DR3 with TL1A induces costimulation of T cells [5, 7, 11, 14] and the TL1A/DR3 axis is implicated in regulatory mechanisms of adaptive immune response under physiological and pathological settings [15] In contrast with this activating function, we have recently showed that TL1A negatively regulates proliferation of B cells activated by BCR stimulation and IL-2 [6]

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