Thymic stromal lymphopoietin (TSLP) was first identified as a growth factor in the conditioned medium supernatant from the Z210R.1 thymic stromal cell line to support B cell proliferation
in vitro [
1,
2]. TSLP is now known to play a key role in the initiation of asthma [
3,
4]. TSLP shares IL-7Rα with IL-7. TSLP signaling is mediated by a heterodimeric receptor complex, which consists of the interleukin-7 receptor α chain (IL-7Rα) and a unique TSLP-binding receptor (TSLPR), to transmit proliferative signals in cells [
5‐
7]. IL-7 binds to a heterodimeric receptor complex, the IL-7Rα and the cytokine receptor common gamma chain (γ
c), which is shared by IL-2, 4, 7, 9, 15 and 21. Both TSLP and IL-7 can activate the transcription factor STAT5. In the IL-7 receptor complex, IL-7Rα binds to Jak1 and γ
c binds to Jak3 upon addition of IL-7. However, none of Jak kinases have been reported to be phosphorylated by the binding of TSLP to its receptor [
2]. Previous studies showed that Y449 in the IL-7Rα cytoplasmic domain provides a docking site for PI-3K and STAT5 and is required for a proliferative signal by IL-7 signaling [
8‐
10]. Further, the tyrosine residues of γ
c are not required for IL-7-mediated cell proliferation [
11]. Isaksen and colleagues observed that the lone tyrosine residue of the mouse TSLPR cytoplasmic domain is required for TSLP-mediated cell proliferation using chimeric receptors composed of the human GM-CSFR α chain extracellular domain fused to the mouse TSLPR transmembrane and cytoplasmic domains and the human GM-CSFR β chain extracellular domain fused to the mouse IL-7Rα transmembrane and cytoplasmic domains [
12]. Brown et al. showed that anti-IL-7Rα antibodies inhibited TSLP-mediated proliferation of pre B-leukemia [
13], indicating that both IL-7Rα and TSLPR contribute to TSLP-dependent cell proliferation.
We aligned the protein sequences of IL-7Rα and TSLPR cytoplasmic domains and observed that Y449 and Y456 of human IL-7Rα and Y368 of human TSLPR were conserved across the species examined while Y401 of human IL-7Rα was not conserved. Because the role of tyrosine residues in the context of the 'native' form TSLP receptor complex in TSLP-mediated cell proliferation has not been previously investigated, we took a systematic approach to evaluate the role of cytoplasmic tyrosine residues of TSLP receptor complex in mediating TSLP-induced cell proliferation. Our data show that the cytoplasmic tyrosine residues of either human IL-7Rα or human TSLPR can mediate TSLP-induced cell proliferation and that mutation of all the four cytoplasmic tyrosine residues of human IL-7Rα and human TSLPR to phenylalanine residues is required to abolish TSLP-dependent cell proliferation.