Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome

TY - JOUR

T1 - Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome

AU - Rensing-Ehl, Anne

AU - Allgäuer, Andrea

AU - Schreiner, Elisabeth

AU - Lorenz, Myriam Ricarda

AU - Rohr, Jan

AU - Klemann, Christian

AU - Fuchs, Ilka

AU - Schuster, Volker

AU - von Bueren, André O

AU - Naumann-Bartsch, Nora

AU - Gambineri, Eleonora

AU - Siepermann, Kathrin

AU - Kobbe, Robin

AU - Nathrath, Michaela

AU - Arkwright, Peter D

AU - Miano, Maurizio

AU - Stachel, Klaus-Daniel

AU - Metzler, Markus

AU - Schwarz, Klaus

AU - Kremer, Anita N

AU - Speckmann, Carsten

AU - Ehl, Stephan

AU - Mackensen, Andreas

N1 - © 2016 by The American Society of Hematology.

PY - 2016/7/14

Y1 - 2016/7/14

N2 - Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.

AB - Autoimmune lymphoproliferative syndrome (ALPS) is a human disorder characterized by defective Fas signaling, resulting in chronic benign lymphoproliferation and accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. Although their phenotype resembles that of terminally differentiated or exhausted T cells, lack of KLRG1, high eomesodermin, and marginal T-bet expression point instead to a long-lived memory state with potent proliferative capacity. Here we show that despite their terminally differentiated phenotype, human ALPS DNT cells exhibit substantial mitotic activity in vivo. Notably, hyperproliferation of ALPS DNT cells is associated with increased basal and activation-induced phosphorylation of serine-threonine kinases Akt and mechanistic target of rapamycin (mTOR). The mTOR inhibitor rapamycin abrogated survival and proliferation of ALPS DNT cells, but not of CD4(+) or CD8(+) T cells in vitro. In vivo, mTOR inhibition reduced proliferation and abnormal differentiation by DNT cells. Importantly, increased mitotic activity and hyperactive mTOR signaling was also observed in recently defined CD4(+) or CD8(+) precursor DNT cells, and mTOR inhibition specifically reduced these cells in vivo, indicating abnormal programming of Fas-deficient T cells before the DNT stage. Thus, our results identify the mTOR pathway as a major regulator of lymphoproliferation and aberrant differentiation in ALPS.

KW - Journal Article

U2 - 10.1182/blood-2015-11-685024

DO - 10.1182/blood-2015-11-685024

M3 - SCORING: Journal article

C2 - 27099149

VL - 128

SP - 227

EP - 238

JO - BLOOD

JF - BLOOD

SN - 0006-4971

IS - 2

ER -