S. Grundstrom et al., IL-2 unresponsiveness in anergic CD4(+) T cells is due to defective signaling through the common gamma-chain of the IL-2 receptor, J IMMUNOL, 164(3), 2000, pp. 1175-1184
Repeated administration of the superantigen staphylococcal enterotoxin A to
mice transduces a state of anergy in the CD4(+) T cell compartment, charac
terized by inhibition of IL-2 production and clonal expansion in vivo. In c
ontrast to what has been reported on anergic T cell clones in vitro, cultur
e of in vivo anergized CD4(+) T cells in the presence of exogenous IL-2 did
not overcome the block in responsiveness. In this study, we demonstrate th
at CD4(+) T cells from mice anergized with staphylococcal enterotoxin A als
o exhibit a reduced proliferative capacity in response to IL-7 and IL-15, c
ytokines that share a common gamma-chain with the IL-2R. Flow-cytometric an
alysis revealed only modest changes in the expression of the different IL-2
R chains. In a number of experiments, our results also provide evidence tha
t excludes a major role of the IL-2R Lu-chain in this system. According to
these results, the inability of anergic cells to respond to IL-2 is not mai
nly due to a down-regulation of the high affinity IL-2R, but to a perturbat
ion in intracellular signaling. Our study confirmed that the activation and
tyrosine phosphorylation of Janus-associated kinase 3 and STAT5 were consi
derably weaker after anergy induction. Moreover, anergic CD4(+) T cells sho
wed significantly reduced DNA-binding ability to STAT5-specific elements, T
aken together, we suggest that the observed IL-2 unresponsiveness in anergi
c CD4(+) T cells could be due to a defect in signaling through the common g
amma-chain of the IL-2R.