Abstract
BackgroundThymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine, which plays an important role in the regulation of immune responses to allergens. TSLP binds to a heterodimeric receptor complex composed of the IL-7 receptor α chain (IL-7Rα) and the TSLP receptor (TSLPR, also known as CRLF2). It has previously been suggested that the lone tyrosine residue in the mouse TSLPR cytoplasmic domain is required for cell proliferation using chimeric receptor systems. Also the role of tyrosine residues in the IL-7Rα cytoplasmic domain in TSLP signaling has not yet been investigated. We undertook a systematic analysis to test the role of tyrosine residues of both the IL-7Rα and the TSLPR in inducing cell proliferation in a growth factor dependent cell line, Ba/F3.ResultsA multiple sequence alignment of the IL-7Rα and TSLPR cytoplasmic domains revealed conservation of most, but not all, cytoplasmic tyrosine residues across several species. Our site-directed mutagenesis experiments revealed that the single tyrosine residue in human TSLPR was not required for TSLP-dependent cell proliferation. It has previously been reported that Y449 of human IL-7Rα is required for IL-7 dependent proliferation. Interestingly, in contrast to IL-7 signaling, none of tyrosine residues in the human IL-7Rα cytoplasmic domain were required for TSLP-dependent cell proliferation in the presence of a wild type TSLPR. However, the mutation of all cytoplasmic four tyrosine residues of human IL-7Rα and human TSLPR to phenylalanine residues abolished the proliferative ability of the TSLP receptor complex in response to TSLP.ConclusionThese results suggest that TSLP requires at least one cytoplasmic tyrosine residue to transmit proliferative signals. Unlike other members of IL-2 cytokine family, tyrosine residues in IL-7Rα and TSLPR cytoplasmic domains play a redundant role in TSLP-mediated cell growth.
Highlights
Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine, which plays an important role in the regulation of immune responses to allergens
Isaksen and colleagues observed that the lone tyrosine residue of the mouse TSLP-binding receptor (TSLPR) cytoplasmic domain is required for TSLP-mediated cell proliferation using chimeric receptors composed of the human GM-CSFR a chain extracellular domain fused to the mouse TSLPR transmembrane and cytoplasmic domains and the human GM-CSFR b chain extracellular domain fused to the mouse IL-7 receptor a chain (IL-7Ra) transmembrane and cytoplasmic domains [12]
Because tyrosine residues play an important role in mediating the signaling by cytokine receptors and are conserved in the IL-7Ra and TSLPR cytoplasmic domains, we wanted to examine the role of these tyrosine residues in TSLP-dependent cell proliferation
Summary
Thymic stromal lymphopoietin (TSLP) is an interleukin-7 (IL-7) like cytokine, which plays an important role in the regulation of immune responses to allergens. TSLP signaling is mediated by a heterodimeric receptor complex, which consists of the interleukin-7 receptor a chain (IL-7Ra) and a unique TSLP-binding receptor (TSLPR), to transmit proliferative signals in cells [5,6,7]. IL-7 binds to a heterodimeric receptor complex, the IL-7Ra and the cytokine receptor common gamma chain (gc), which is shared by IL-2, 4, 7, 9, 15 and 21 Both TSLP and IL-7 can activate the transcription factor STAT5. 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 a chain extracellular domain fused to the mouse TSLPR transmembrane and cytoplasmic domains and the human GM-CSFR b chain extracellular domain fused to the mouse IL-7Ra transmembrane and cytoplasmic domains [12]. Brown et al showed that anti-IL-7Ra antibodies inhibited TSLP-mediated proliferation of pre B-leukemia [13], indicating that both IL-7Ra and TSLPR contribute to TSLP-dependent cell proliferation
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