Icos y su ligando icos-l en la homeostasis y fisiología de l as células nk

Resumen

ICOS participates in the development and activation of T and NKT lymphocytes; however, although the expression of ICOS is inducible in NK and participates in its functional processes, its role in NK biology is not fully understood. Using ICOS-KO mice, the role of ICOS in NK cell homeostasis, maturation and function has been analyzed in this Thesis. Here, we show that ICOS-KO mice have a lower proportion and number of NK cells (CD3-NK1.1+) in the bone marrow and the spleen, and an increased rate of apoptosis in these cells, suggesting a possible role of ICOS in NK cell homeostasis. The expression of ICOS can be detected during the maturation process in the bone marrow, in a small fraction of NK cells from the immature CD122+NK1.1- stage. ICOS expression increases after the acquisition of the NK1.1 marker and is further increased in the presence of different stimuli, as IL-2. ICOS-KO mice show defects in the development of NK cells in both bone marrow and spleen. Thus, ICOS expression is necessary for the proper development of these cells. This altered pattern results in an increase of NK cells in the most immature compartments during the development of this cells in ICOS-KO mice. Associated changes have also been found in the expression of different effector molecules and functional markers such as CD107a (LAMP), Ly49D, KLRG1 or different NK effector cytokines, as IFN-γ or TNF-α. Lack of ICOS has revealed that it modulates the expression of its own ligand (ICOS-L), since ICOS-KO animals have an increased expression of this marker. Increased ICOS-L expression is observed in antigen presenting cells, such as B cells, where ICOS-L expression is well established, but also in NK cells. In this line we have found that both types of cells, NK and DC, are able to express both molecules, ICOS and ICOS ligand. This fact provides the co-stimulatory pair ICOS:ICOS-L of a particular relevance in the fundamental role of the NK:DC crosstalk in the coordination of innate and adaptive immune responses. The importance of ICOS and ICOS-L binding in the function of NK cells has been demonstrated by analyzing the cytotoxic capacity of cells, as well as in activation assays using antibody or specific fusion proteins, or in the analysis of the immune response in vivo. All these results reveal an implication of ICOS: ICOS-L in the homeostasis, development and function of mouse NK cells, one of the key populations in the immune response, since this cellular population, besides having an indisputable role in the control of infections and tumors, may be crucial in the control of other lymphoid subpopulations during tumor immune response and also in the control of infectious and inflammatory diseases.