Selective Regulation of CD8 Effector T Cell Migration by the p110γ Isoform of Phosphatidylinositol 3-Kinase

Abstract

Chemokine-mediated T cell migration is essential to an optimal immune response. The p110γ isoform of PI3K is activated by G protein-coupled receptors and regulates neutrophil and macrophage chemotaxis. We used p110γ-deficient mice to examine the role of p110γ in CD8 T cell migration and activation in response to viral challenge. Naive CD8 T cell migration in response to CCL21 in vitro and trafficking into secondary lymphoid organs in vivo was unaffected by the loss of p110γ. Furthermore, loss of p110γ did not affect CD8 T cell proliferation and effector cell differentiation in vitro in response to anti-CD3 stimulation or in vivo in response to vaccinia virus (VV) challenge. However, there was reduced migration of p110γ knockout (p110γ−/−) CD8 effector T cells into the peritoneum following i.p. challenge with VV. The role of p110γ in CD8 effector T cell migration was intrinsic to T cells, as p110γ−/− CD8 effector T cells exhibited impaired migration into the inflamed peritoneum following secondary transfer into wild-type recipients. In addition, p110γ−/− CD8 effector T cells exhibited impaired migration in vitro in response to inflammatory chemoattractants. Although wild-type mice efficiently cleared VV at high viral doses, infection of p110γ knockout mice resulted in visible illness and death less than a week after infection. Thus, p110γ is dispensable for constitutive migration of naive CD8 T cells and subsequent activation and differentiation into effector CD8 T cells, but plays a central role in the migration of effector CD8 T cells into inflammatory sites.

Stat1 stimulates cap-independent mRNA translation to inhibit cell proliferation and promote survival in response to antitumor drugs

“…6). Apart from acting in a cell-autonomous manner, Stat1 may increase PI3Kγ to regulate immune responses given that both proteins are involved in the activation of natural killer (NK) and CD8 T cells (70)(71)(72)(73). Considering the implications in cancer treatment, Stat1's response to chemotherapeutic drugs is likely to be controlled by both cell-autonomous and immune regulatory mechanisms.…”

PI3K signalling in lymphocyte migration

“…13,28 Moreover, following injection of vaccinia virus into the peritoneum, p110δ-deficient effector CD8 T cells and NK cells have impaired migration to the infection site. 32 These isoforms have also distinct roles in regulation of leukocyte functions, p110γ being involved in mast cell degranulation 33 and thymocyte development 34 and p110δ shown to regulate B cell development and activation, 35,36 mast cell degranulation upon IgE receptor cross-linking 30 but also T cell proliferation and differentiation 37 as well as regulatory T cell activity. 38 This suggests that PI3K-dependent leukocyte functions might be regulated by different catalytic PI3K isoforms depending, not only on the cell type, but also on the context.…”

CCL21 mediates CD4+ T-cell costimulation via a DOCK2/Rac-dependent pathway

“…29 Furthermore, PI3K isoforms are involved in DOCK2-independent chemokine-induced lymphocyte migration. 30,31 PI3K␥ has also been reported to contribute to T-cell proliferation in some 32,33 but not all studies. 31 PI3K␦ is a major class IA isoform expressed in immune cells and is activated by tyrosine kinases downstream T-and B-cell antigen receptors.…”