Cytokine signal transduction is suppressed in preselection double-positive thymocytes and restored by positive selection.
Death by neglect requires that CD4+8+ double-positive (DP) thymocytes avoid cytokine-mediated survival signals, which is presumably why DP thymocytes normally extinguish IL-7R gene expression. We report that DP thymocytes before positive selection (preselection DP thymocytes) fail to transduce IL-7 signals even when they express high levels of transgenic IL-7R on their surface, because IL-7R signal transduction is actively suppressed in preselection DP thymocytes by suppressor of cytokine signaling (SOCS)-1. SOCS-1 is highly expressed in preselection DP thymocytes, but it is down-regulated by T cell receptor-mediated positive selection signals. Interestingly, we found that the uniquely small cell volume of DP thymocytes is largely the result of absent IL-7 signaling in preselection DP thymocytes. We also report that, contrary to current concepts, preselection DP thymocytes express high levels of endogenously encoded IL-4Rs. However, their ability to transduce cytokine signals is similarly suppressed by SOCS-1. Thus, despite high surface expression of transgenic or endogenous cytokine receptors, cytokine signal transduction is actively suppressed in preselection DP thymocytes until it is restored by positive selection.
Yu
Qing
Q
Experimental Immunology Branch, National Cancer Institute (NCI), Bethesda, MD 20892, USA.
Park
Jung-Hyun
JH
Doan
Loretta L
LL
Erman
Batu
B
Feigenbaum
Lionel
L
Singer
Alfred
A
D000818:Animals; D015704:CD4 Antigens; D016827:CD8 Antigens; D002352:Carrier Proteins / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D015847:Interleukin-4 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism*; D020395:Receptors, Interleukin-7 / Q000276:immunology / Q000378:metabolism*; D012097:Repressor Proteins / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000276:immunology / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D053662:Interleukin-4 Receptor alpha Subunit
D015704:CD4 Antigens; D016827:CD8 Antigens; D002352:Carrier Proteins; D015847:Interleukin-4; D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell; D011956:Receptors, Cell Surface; D020395:Receptors, Interleukin-7; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit; C491590:Socs1 protein, mouse; C415350:interleukin-7 receptor, alpha chain