Dr. Nan-Shih Liao 廖南詩博士

Research

Interleukin 15 and T Cell Biology

Interleukin 15 (IL-15) was discovered by its ability to support T cell growth, and later found to be a pleiotropic cytokine with wide tissue distribution. IL-15 receptor (IL-15R) consists of α, β, and γ chains. IL-15Rβγ binds IL-15 as well as IL-2 with intermediate affinity. IL-15Rα is private, binds IL-15 with high affinity and is widely expressed as its ligand. Despite of certain shared function between IL-15 and IL-2 due to the shared βγ nreceptor chains, Il15rα-/- and Il15^-/- mice exhibit a phenotype distinct from Il2rα^-/- and Il2^-/- mice. Il15rα^-/- and Il15^-/- mice are deficient in CD8⁺ T cells, CD8αα⁺ intestinal intraepithelial lymphocytes (iIEL) and NK cells, but do not develop the early-onset lethal autoimmune disease that characterizes Il2rα^-/- and Il2-/- mice. The unique phenotype of Il15rα-/- and Il15-/- mice indicates unique function of the IL-15 cytokine system and implicates a critical role of IL-15Rα in IL-15 function. We have studied function of the IL-15 system in T cell development, activation and survival.

I. The IL-15 system and CD4⁺ T cell development and activation.

We found IL-15Rα is a negative regulator of TCRmediated activation of CD4⁺ T cells in vitro and in vivo. Moreover, aged female Il15rα^-/- mice develop lupus-like symptoms, including splenomegaly and autoantibody production. Whereas the development and function of natural occurring CD4⁺CD25⁺ Treg cells in Il15rα^-/- mice appear normal, CD4⁺ T cells of female Il15rα^-/- mice are autoreactive in vitro and mediate autoimmune response when transferred into wild type mice. Examination of thymocyte negative selection reveals normal selection by high-affinity self-antigens but inefficient selection by low-affinity self-antigens in Il15rα^-/- mice. This abnormality may result in more auto-reactive T cells in Il15rα^-/- mice compared to wt mice, which contributes to the late-onset autoimmune phenotype. We are dissecting the cellular mechanism of how the IL-15 system affects thymocyte negative selection.

II. The IL-15 system and CD8αα⁺ iIEL homeostasis.

Mice devoid of the IL-15 system lose over 90% of CD8αα+ TCRαβ (αβ) and γδ iIEL. Previous work reveals that IL-15Rα and IL-15 expressed by parenchymal cells, but not by bone marrow-derived cells, are required for normal CD8αα⁺ iIEL homeostasis. However, it remains unclear when and how the IL-15 system affects CD8αα⁺ iIEL through their development. We found that IL-15Rα is dispensable for CD8αα⁺ αβ and γδ iIEL development in the thymus, but is required for the maintenance and/or differentiation of the lineage marker negative precursors in the intestinal epithelium, especially for the most mature CD8 single positive subset. Moreover, the IL-15 system supports the survival of mature CD8αα⁺ iIEL in vivo. The IL-15 system thus regulates CD8αα⁺ iIEL homeostasis at both precursor and mature cell stages in the intestine. We are investigating the cellular and molecular mechanisms underlying the IL-15-mediated survival of CD8αα⁺ iIEL.