Signaling by intrathymic cytokines, not T cell antigen receptors, specifies CD8 lineage choice and promotes the differentiation of cytotoxic-lineage T cells

Jung-Hyun Park et al. Nat. Immunol. 11:257-265, 2010

Speaker: Tsung-Hao Chang (張琮浩)                                   Time: 13:10-14:00, Oct. 13, 2010

Commentator: Dr. Pin Ling (凌斌 老師)                             Place: Room 601

Abstract

T cell differentiation constitutes multiple steps including homing of progenitor cells from bone marrow to thymus and differentiaton from CD4^-CD8^- double negative (DN) cells to CD4⁺CD8⁺ double positive (DP) cells, and finally CD4⁺ or CD8⁺ single positive (SP) cells.  DP thymocytes undergo positive and negative selection, and then differentiate to either CD4⁺ or CD8⁺ SP cells.  To describe how DP cells decide to become CD4⁺ or CD8⁺ SP cells (CD4/CD8-lineage choice), the kinetic signaling model has previously proposed that DP cells first differentiate to CD4⁺CD8^lowbipotent intermediate cells after TCR signal-mediated positive selection¹.  The differentiation of CD4⁺CD8^low intermediate cells into CD4⁺ or CD8⁺ SP cells is decided by TCR signal duration from MHC class I or II molecules and some undefined intrathymic cytokine signaling.  In this paper, the authors suggested that intrathymic γ_c cytokines (e.g. IL-7 and IL-4) were the key factors in CD8 lineage choice rather than TCR signaling.  The blockade of intrathymic cytokine signaling in DP-specific Stat5 knockout mice and SOCS1-transgenic mice impeded CD8 lineage choice.  The authors further confirmed that γ_c cytokine signaling induced the expression of RUNX3, a CD8 lineage choice factor, to insure CD8 lineage even without TCR signaling.  However, transgenic expression of IL-7 receptor failed to drive the differentiation of DP cells into CD8⁺ SP cells in SOCS1-KO-ZAP70-KO mice.  The authors suggested that in vivo TCR-mediated positive selection signaling stimulated cytokine-unresponsive DP cells to express IL-7 receptor and CCR7, thus helping these TCR-signaled DP cells migrate to IL-7-rich medulla and then differentiate into CD8⁺ SP cells after IL-7 stimulation.  In conclusion, this study provides clear evidence that, during positive selection, TCR signaling converts DP cells into IL-7-responsive thymocytes and the intrathymic IL-7 signaling specifies CD8 lineage choice of cytotoxic T cells.

Reference:

1.      Alfred Singer, Stanley Adoro and Jung‑Hyun Park. Lineage fate and intense debate: myths, models and mechanisms of CD4- versus CD8-lineage choice. Nat. Rev. Immunol. 8:788-801, 2008