CD44 Regulates Survival and Memory Development in Th1 Cells

Bas J.G. Baaten., et al. 2010. Immunity. 32, 104-15

Speaker: Chia-Yun Wu (吳佳芸)                       Time: 14:10~15:00, Jun. 09, 2010

Commentator: Dr. Yee-Shin Lin (林以行 博士)        Place: Room 601

Abstract:

As pathogens invade host cells, the local antigen-presenting cells (APCs) catch and present peptide:MHC complex on cell surface in the draining lymph node. The APCs activate naïve T cells, which will expand and differentiate into effector T cells. Most of theeffector T cells undergo cell-mediated apoptosis, only a few effector T cells become memory T cells. CD44 is a cell surface glycoprotein, a receptor for the glycosaminoglycan hyaluronic acid (HA), and CD44 can regulate proliferation and apoptosis in different cancer cells¹. After the activation of naïve T cells by antigen recognition, the CD44 expression increases. Higher level of CD44 expression was detected in memory T cells than naïve T cells ². However the physiological function of CD44 in memory T cells is unknown. In the study, the authors found that memory response lost in CD44^-/- T cells using a murine model with influenza virus infection. The immune responses include antigen recognition stage, lymphocyte activation stage (clonal expansion and differentiation), antigen elimination stage and contraction stage. The authors found that it was not due to the failure to initial priming, clonal expansion or effector function, but due to that CD44 helped to promote the survival of activated CD4⁺ T cells in contraction stage. Previous studies showed that CD44 is associated with the resistance to Fas-mediated cell death¹. Using Annexin V binding assay, they showed that activated CD44^-/- CD4⁺ T cells underwent apoptosis after expansion. Activated caspase 8 also increased in activated CD44^-/- CD4⁺ T cells. Activated CD4⁺ T cells differentiate into distinct subset effector T cells induced by different transcription factors and cytokines. They found that CD44 regulated CD4 Th1 cells survival, but not for CD4⁺ Th2, Th17 cells. Treating CD4⁺ Th1 cells with CD44 agonist antibody showed that signaling through CD44 enhanced cell survival after CD4 T cells expansion. Ligation of CD44 contributed to activation of the PI3K-Akt pathway³ of Th1 cells. In summary, CD44 is essential for promoting Th1 effector cells survival to generate memory Th1 cells by inhibiting Fas-mediated cell death.

References:

1. Hauptschein, R.S. et al., 2005. Functional proteomic screen identifies a modulating role for CD44 in death receptor-mediated apoptosis. Cancer Res. 65, 1887–1896.

2. Pure´ , E., and Cuff, C.A. 2001. A crucial role for CD44 in inflammation. Trends Mol. Med. 7, 213–221.

3. Klingbeil, P., et al., 2009. CD44 variant isoforms promote metastasis formation by a tumor cell-matrix cross-talk that supports adhesion and apoptosis resistance. Mol.Cancer Res. 7, 168–179.