CXCR4 acts as a costimulator during thymic β-selection

Paul C. Trampont et al., Nat. Immunol. 11:162-72, 2010

Speaker: Tsung-Hao Chang (張琮浩)                                   Time: 15:00-16:00, Jun. 9, 2010

Commentator: Dr. Yea-Lih Lin (林雅俐 老師)                   Place: Room 601

Abstract

T cell differentiation constitutes multiple steps including homing of progenitor cells from bone marrow to thymus and differentiating form CD4^-CD8^- double negative cells (DN) to CD4⁺CD8⁺ double positive cells (DP), and finally CD4⁺ or CD8⁺ single positive cells (SP).    CXCR4, a chemokine receptor, has been reported to play critical roles in embryogenesis, cardiogenesis and hematopoiesis¹. However, how CXCR4 signaling affects the thymocyte differentiation is poorly understood.  The location of thymocytes in thymus is very important for their differentiation.  At the DN3 stage, thymocytes undergo TCR_β chain rearrangement and those who successfully express pre-TCR complex can pass the checkpoint (β-selection) for further maturation.  The authors found that the blockade of CXCR4 signaling resulted in a defect of thymocyte differentiation at the DN3 stage.  Cxcr4 deficient DN3 thymocytes underwent excessive apoptosis and had aberrant localization.  The pre-TCR-mediated survival signaling could not rescue the differentiation defect of DN3 thymocytes in Lck-Cre⁺ Cxcr4^fl/fl mice.  The authors determined that CXCR4 functioned as a costimulator with pre-TCR signaling to regulate anti-apoptotic molecule Bcl2A1 in DN3 thymocytes².  The pre-TCR signaling was also required for CXCR4-mediated chemotaxis to SDF-1α, a natural ligand for CXCR4.  SDF1-α treatment induced colocalization of pre-TCR, suggesting that CXCR4 acts as a co-stimulator for pre-TCR.  Also, the blockade of pre-TCR impaired CXCR4-mediated chamotaxis through ERK pathway.  Finally, the authors showed that Shc is an essential downstream compartment of CXCR4 signaling to induce ERK phosphorylation and actin polymerization.  The Lck-Cre⁺ shc1^fl/fl thymocytes showed similar phenotypes to Lck-Cre⁺ Cxcr4^fl/fl thymocytes.  In conclusion, CXCR4, a well-known chemokine receptor, acts as a costimulator of pre-TCR and regulates the locatlization and survival of thymocyte during β-selection.

References

1.      Plotkin, J. et al. Critical role for CXCR4 signaling in progenitor localization and T cell differentiation in the postnatal thymus. J. Immunol. 171:4521-27, 2003.

2.      Mandal, M. et al. The BCL2A1 gene as a pre-T cell receptor-induced regulator of thymocyte survival. J. Exp. Med. 201:603–614, 2005.