Regulating the immune system via IL-15 transpresentation

Abstract

Transpresentation has emerged as an important mechanism mediating IL-15 responses in a subset of lymphocytes during the steady state. In transpresentation, cell surface IL-15, bound to IL-15Rα is delivered to opposing lymphocytes during a cell-cell interaction. The events most dependent on IL-15 include the development and homeostasis of memory CD8 T cells, Natural Killer cells, invariant Natural Killer T cells, and intraepithelial lymphocytes. As lymphocyte development and homeostasis involve multiple steps and mechanisms, IL-15 transpresentation can have diverse roles throughout. Moreover, distinct stages of lymphocyte differentiation require IL-15 transpresented by different cells, which include both hematopoietic and non-hematopoietic cell types. Herein, we will describe the points where IL-15 transpresentation impacts these processes, the specific cells thought to drive IL-15 responses, as well as their role in the course of development and homeostasis.

Figure 1. IL-15 transpresentation during CD8 T cell differentiation

Cartoon depicts various cell types transpresenting IL-15 through the differentiation of CD8 T cells. Cell surface IL-15Rα (dark blue) is shown presenting IL-15 (light blue diamond) in trans to IL-15Rβ/γC receptor complex (red/orange subunits) on the T cells. Naïve CD8 T cells require IL-15 for survival and receive this signal from unidentified hematopoietic and radiation-resistant stromal cells. T cell activation induces the differentiation of effector CD8 T cells, which does not require IL-15 transpresentation. As effector cells transition into memory CD8 T cells, macrophages transpresenting IL-15 facilitate survival and further differentiation into memory CD8 T cells. Once memory CD8 T cells are generated, DCs transpresenting IL-15 preferentially support CD62L+ memory CD8 T cells while macrophages preferentially support CD62L- memory CD8 T cells. Transpresentation of IL-15 mediates homeostasis of memory CD8 T cells in part by promoting homeostatic proliferation and survival.

Figure 2. IL-15 transpresentation during iNKT cell development

Cartoon shows proposed scheme of iNKT cell development in the thymus and liver including the cells that transpresent IL-15 at the specific stages. iNKT cells transition from CD44^low NK1.1⁻ T cells (stage I) to CD44^high NK1.1⁻ T cells (stage II) and then finally into CD44^high NK1.1⁺ T cells(stage III). In the thymus, IL-15 transpresentation is crucial for either the differentiation and/or survival of stage III (CD44^high NK1.1⁺) iNKT cells and is provided by medullary thymic epithelial cells. Some stage II iNKT cells (CD44^high NK1.1⁻) leave the thymus and migrate to the liver where their survival, proliferation, and differentiation is supported by IL-15 transpresented by Kupffer cells, non-hematopoietic Stellate cells, DCs. DCs transpresenting IL-15 can also promote functional maturation of iNKT cells, making them capable of producing IFN-γ as well as induce homeostatic proliferation.

Figure 3. IL-15 transpresentation during NK cell development

NK cell development begins as common lymphoid progenitors differentiate into NK precursors (NKp) (CD122+NK1.1−), which are the earliest cells to express IL-15Rβ (CD122). NKp then differentiate into immature NK cells (immNK;CD122⁺NK1.1⁺), which require IL-15 transpresentation that is efficiently provided by radiation-resistant stromal cells. Further differentiation into M1 (CD122⁺NK1.1⁺CD11b^low, CD49b⁺) and M2 (CD122⁺NK1.1⁺ CD11b^high, CD27⁺) NK cells requires IL-15 transpresentation mediated primarily by unidentified hematopoietic cells. When M1 and M2 NK cells migrate into the peripheral tissues, such as the spleen and liver, these mature NK cells utilize IL-15 transpresented by both macrophages and DCs for survival, proliferation, and further maturation. Maturation can involve differentiation from the M1 to M2 stage as well as from the M2 stage to an even more mature state, identified by low CD27 expression.