We are exploring new immunotherapic strategies in autoimmune diseases and antitumor immunity. To this end, the role in immune responses of PI3K isoforms, and particularly of the PI3K p110α catalytic subunit in CD28 and ICOS signals, is under study.

The development of efficient immune responses depend on signals delivered by specific cell membrane receptors that are coordinated with signals from other surface molecules generically termed costimulatory (signal 2) plus signals from cytokine and chemoquine receptors (signal 3). Class I phosphatidyl Inositol-3 kinases (PI3K) control cell growth, proliferation, differentiation, and survival. They are activated by receptors specific of innate and adaptive immunity as well as by cytokine and chemoquine receptors or costimulatory molecules.

Among costimulatory signals, those mediated by CD28 family molecules like CD28 or ICOS (CD278) and their B7h family ligands (CD80 and CD86, and ICOS-ligand (ICOS-L, CD275)) are particularly important. Those surface molecules, like CD28 or ICOS, with YxxM motifs, can directly recruit class IA PI3K, like p110α y p110δ, that are abundant in leukocytes. In other cases PI3K are indirectly recruited through adapter molecules. Thus, these molecules have an enormous potential as targets in immunotherapy, which is determined by the expression pattern of the PI3K isoforms and their signaling targets in distinct cell lineages.

In parallel, the mechanisms of ICOS-L signaling are also determined in tumor and non-tumor cells. Recent data show that ICOS-L signals can modify important aspects of cell function including cell migration, maturation and antigen presentation in dendritic cells, or osteoclast differentiation, or the migration and metastasis of human and mouse tumor cells that express the ICOS-L. The effects of ICOS-L on cell migration are mediated by the Rac-1 activator β-PIX and by the FAK tyrosine kinase, indicating its immunomodulatory potential.

Furthermore, the observation that ICOS-dificient (ICOS-KO) mice have low NK cell numbers led us to analyze its role in NK cell development and function. Indeed, NKs can express ICOS, and ICOS-KO mice show deficient NK cell maturation and homeostasis, due to both NK-intrinsic and -extrinsic factors. ICOS-KO NK cells show impaired cytotoxicity and production of IFN-γ, as well as NK cell-mediated efector function in response to poly(I:C) or to vaccinia virus infection in vivo. Interestingly, NK cells can simultaneously express ICOS and its ligand ICOS-L, and both are functional in costimulation of NK activation signals. These data confirm the immunomodulatory potential of CD28 family molecules in innate immune cells.