Differential postselection proliferation dynamics of αβ T cells, Foxp3+ regulatory T cells, and invariant NKT cells monitored by genetic pulse labeling
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Differential postselection proliferation dynamics of αβ T cells, Foxp3+ regulatory T cells, and invariant NKT cells monitored by genetic pulse labeling. / Föhse, Lisa; Reinhardt, Annika; Oberdörfer, Linda; Schmitz, Susanne; Förster, Reinhold; Malissen, Bernard; Prinz, Immo.
In: J IMMUNOL, Vol. 191, No. 5, 01.09.2013, p. 2384-92.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Differential postselection proliferation dynamics of αβ T cells, Foxp3+ regulatory T cells, and invariant NKT cells monitored by genetic pulse labeling
AU - Föhse, Lisa
AU - Reinhardt, Annika
AU - Oberdörfer, Linda
AU - Schmitz, Susanne
AU - Förster, Reinhold
AU - Malissen, Bernard
AU - Prinz, Immo
PY - 2013/9/1
Y1 - 2013/9/1
N2 - The thymus generates two divergent types of lymphocytes, innate and adaptive T cells. Innate T cells such as invariant NKT cells provide immediate immune defense, whereas adaptive T cells require a phase of expansion and functional differentiation outside the thymus. Naive adaptive T lymphocytes should not proliferate much after positive selection in the thymus to ensure a highly diverse TCR repertoire. In contrast, oligoclonal innate lymphocyte populations are efficiently expanded through intrathymic proliferation. For CD4(+)Foxp3(+) regulatory T cells (Tregs), which are thought to be generated by agonist recognition, it is not clear whether they proliferate upon thymic selection. In this study, we investigated thymic and peripheral T cell proliferation by genetic pulse labeling. To this end, we used a mouse model in which all developing αβ thymocytes were marked by expression of a histone 2B-enhanced GFP (H2BeGFP) fusion-protein located within the Tcrd locus (TcrdH2BeGFP). This reporter gene was excised during TCR α-chain VJ-recombination, and the retained H2BeGFP signal was thus diluted upon cell proliferation. We found that innate T cells such as CD1d-restricted invariant NKT cells all underwent a phase of intense intrathymic proliferation, whereas adaptive CD4(+) and CD8(+) single-positive thymocytes including thymic Tregs cycled, on average, only once after final selection. After thymic exit, retention or loss of very stable H2BeGFP signal indicated the proliferative history of peripheral αβ T cells. There, peripheral Tregs showed lower levels of H2BeGFP compared with CD4(+)Foxp3(-) T cells. This further supports the hypothesis that the Treg repertoire is shaped by self-Ag recognition in the steady-state.
AB - The thymus generates two divergent types of lymphocytes, innate and adaptive T cells. Innate T cells such as invariant NKT cells provide immediate immune defense, whereas adaptive T cells require a phase of expansion and functional differentiation outside the thymus. Naive adaptive T lymphocytes should not proliferate much after positive selection in the thymus to ensure a highly diverse TCR repertoire. In contrast, oligoclonal innate lymphocyte populations are efficiently expanded through intrathymic proliferation. For CD4(+)Foxp3(+) regulatory T cells (Tregs), which are thought to be generated by agonist recognition, it is not clear whether they proliferate upon thymic selection. In this study, we investigated thymic and peripheral T cell proliferation by genetic pulse labeling. To this end, we used a mouse model in which all developing αβ thymocytes were marked by expression of a histone 2B-enhanced GFP (H2BeGFP) fusion-protein located within the Tcrd locus (TcrdH2BeGFP). This reporter gene was excised during TCR α-chain VJ-recombination, and the retained H2BeGFP signal was thus diluted upon cell proliferation. We found that innate T cells such as CD1d-restricted invariant NKT cells all underwent a phase of intense intrathymic proliferation, whereas adaptive CD4(+) and CD8(+) single-positive thymocytes including thymic Tregs cycled, on average, only once after final selection. After thymic exit, retention or loss of very stable H2BeGFP signal indicated the proliferative history of peripheral αβ T cells. There, peripheral Tregs showed lower levels of H2BeGFP compared with CD4(+)Foxp3(-) T cells. This further supports the hypothesis that the Treg repertoire is shaped by self-Ag recognition in the steady-state.
KW - Adoptive Transfer
KW - Animals
KW - Cell Differentiation/immunology
KW - Cell Proliferation
KW - Flow Cytometry
KW - Forkhead Transcription Factors/immunology
KW - Mice
KW - Mice, Inbred C57BL
KW - Natural Killer T-Cells/cytology
KW - Receptors, Antigen, T-Cell, alpha-beta/immunology
KW - T-Lymphocyte Subsets/cytology
KW - T-Lymphocytes, Regulatory/cytology
U2 - 10.4049/jimmunol.1301359
DO - 10.4049/jimmunol.1301359
M3 - SCORING: Journal article
C2 - 23894200
VL - 191
SP - 2384
EP - 2392
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 5
ER -