Coupled IL-2-dependent extracellular feedbacks govern two distinct consecutive phases of CD4 T cell activation.
T cells integrate cell-specific Ag receptor signaling with shared signals mediated by secreted cytokines, which often involve regulatory feedback loops. IL-2 signaling, for example, reduces the synthesis of IL-2 and increases the synthesis of IL-2Rα-chain, whereas both genes require TCR signaling for their activation. The ways by which T cells dynamically integrate these private and public signals during activation are not well understood. We combined robotics, multiparameter flow cytometry, and real-time quantitative PCR to analyze T cell activation at high temporal resolution over several days. Two distinct temporal phases of T cell activation were evident. First, Ag-dependent signals activated low IL-2Rα and high IL-2 production, independent of IL-2 signaling. Subsequently, secreted IL-2 acted as a shared resource driving high IL-2Rα expression, reduced IL-2 synthesis, and cell proliferation. This transition was independent of continued TCR signaling. Our data allowed the determination of the parameters of the IL-2-mediated extracellular positive and negative feedback circuits and demonstrated that the two loops are coupled and become activated at a similar level of IL-2 signaling. We propose that temporal separation of private and shared signals allows T cells to first integrate Ag-specific responses and subsequently share information leading to collective decision making.
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel.
Nir
N
Waysbort
Dor
D
Russ
Benjamin M
BM
Chain
Nir
N
Friedman
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D025461:Feedback, Physiological / Q000502:physiology*; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000276:immunology; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008809:Mice, Inbred C3H; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D060888:Real-Time Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D012371:Robotics; D013997:Time Factors
D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell