Control of CD4+ T Cell Differentiation and Function by PI3K Isoforms

The phosphoinositide-3-kinase (PI3K) pathway is a highly conserved intracellular signaling pathway involving numerous key effectors which, in response to diverse extracellular stimuli, modulate the phenotype and function of most mammalian cell types in a pleiotropic manner. PI3K signaling plays a critical role in the development, activation, and differentiation of lymphocytes. In particular, the PI3Kδ and PI3Kγ isoforms have been shown to carry out essential, non-redundant roles in T cells, and therefore, tight regulation of the PI3K pathway is important to maintain the balance between immune tolerance and inflammation. Recent and ongoing efforts to manipulate the biology of T helper cell subsets in the treatment of autoimmune conditions, inflammatory disorders, as well as cancer have shown promising results, and targeting the PI3K pathway may be beneficial in these contexts. However, more insight as to the precise function of individual PI3K isoforms in pathogenic and protective immune cell subsets is still required, and how exactly PI3K signaling is regulated and integrated with classical immune pathways. This chapter provides an overview of the role of PI3K isoforms in the differentiation and function of T helper cell subsets, within the broader context of targeting this pathway to potentially alleviate immunopathology.