Regulatory Roels of IL-15R alpha in Homeostasis and Activation of T cells

• Main Authors: Jan-Mou Lee, 李建謀
• Other Authors: Nan-Shih Liao
• Format: Others
• Language: en_US
• Published: 2005
• Online Access: http://ndltd.ncl.edu.tw/handle/19074029822220185098

博士 === 國防醫學院 === 生命科學研究所 === 93 === Abstract Although IL-15 has been reported to be involved in maintenance and activation of T cells in vitro and in vivo, the function of IL-15Rα, its high affinity receptor, remains unclear. Using IL-15Rα-/- and wild type mice, the present work attempts to elucidate the role of IL-15Rα in T cell homeostasis and activation. In respects of homeostasis, IL-15Rα-/- mice exhibited reduced cell numbers and bcl-2 abundance in peripheral CD8+ T but not CD4+ T cells. The enforced expression of bcl-2 in IL-15Rα-/- mice, however, did not restore the reduced levels of peripheral CD8+ T cells, suggesting IL-15Rα sustains homeostasis of peripheral CD8+ T cells by mechanism(s) other than bcl-2-mediated survival. In T cell activation, IL-15Rα negatively regulated activation of CD4+ T cells in response to TCR stimulation in vitro and in vivo. Such negative effects by IL-15Rα on CD4+ T cell activation were further revealed as increasing TCR threshold, diminishing TCR signalling, and impairing follow-up target gene expression, such as IL-2 and IL-2Rα. Contrary to CD4+ T cells, IL-15Rα positively regulated activation, bcl-2 levels, and survival of CD8+ T cells in response to TCR and IL-15 stimulation by predominantly promoting binding affinity of IL-15 to IL-2Rβγc. Reductions in both cell frequencies and functional activities of peripheral CD25+CD4+ regulatory T cells were also found in IL-15Rα-/- mice. Moreover, majority of aged female IL-15Rα-/- mice developed lupus-like symptoms. Taken together, 3 major findings were concluded; 1) IL-15Rα is required for peripheral homeostasis of CD8+ T cell, 2) IL-15Rα positively regulates CD8+ T but negatively regulates CD4+ T cell activation, 3) IL-15Rα is a negative regulator for autoimmunity.