Cutting Edge: Differential Roles for Phosphoinositide 3-Kinases, p110γ and p110δ, in Lymphocyte Chemotaxis and Homing

Abstract

Despite the established role for PI3Ks in cell migration, the PI3Ks involved in lymphocyte chemotaxis are poorly defined. In this study, we report that p110γ-deficient T cells, but not B cells, show reduced chemotactic responses to the lymphoid chemokines, CCL19, CCL21, and CXCL12. As B cell and T cell chemotactic responses were both sensitive to the general PI3K inhibitors, wortmannin (WMN) and LY294002, we explored whether B cell responses were affected in mice lacking p110δ, a major PI3K isoform in lymphocytes. B cells deficient in p110δ showed diminished chemotactic responses, especially to CXCL13. Adoptive transfer experiments with WMN-treated wild-type B cells and with p110δ-deficient B cells revealed diminished homing to Peyer’s patches and splenic white pulp cords. WMN selectively inhibited CXCR5-dependent B cell homing to Peyer’s patches. These observations establish that p110γ and p110δ function in lymphocyte chemotaxis, and show differential roles for PI3K family members in B and T cell migration.

The p110δ Isoform of Phosphoinositide 3-Kinase Controls Clonal Expansion and Differentiation of Th Cells

“…WT and p110␦ D910A/D910A T cells populated peripheral lymph nodes with similar efficiencies (Fig. 4A, day 0 time point), consistent with a nonessential role for p110␦ in T cell migration (31). In response to immunization with OVA in combination with LPS, clonal expansion of p110␦ D910A/D910A T cells was severely reduced in comparison with WT cells (Fig.…”

Analysis of migratory and prosurvival pathways induced by the homeostatic chemokines CCL19 and CCL21 in B-cell chronic lymphocytic leukemia

“…In normal lymphocytes, optimal polarization and migration in response to CCL19, CCL21 or CXCL12 is dependent on the expression of DOCK2, a Rac GTPase exchange factor, and PI3K. Whereas in T cells PI3K-dependent migration is mainly mediated by PI3Kγ, in B cells class IA PI3K is required for their efficient chemotaxis and homing to LNs (7,8).…”

“…Class I PI3Ks are heterodimeric molecules composed by a regulatory and a catalytic subunit that generate phosphatidylinositol-3,4,5-triphosphate (PIP3), which have a key role in cell migration (6). Class I PI3Ks are further subdivided into class IA and class IB isoforms, which are involved in the chemotaxis and homing of B and T lymphocytes, respectively (7,8).…”

Roles for phosphoinositide 3‐kinases, Bruton's tyrosine kinase, and Jun kinases in B lymphocyte chemotaxis and homing

“…Highlighting the difference between B and T cells, B cells require DOCK2 for integrin activation, while T cells do not [8]. A recent study indicated that WMN treatment impaired the entrance of mouse B cells into Peyer's patches and the splenic white pulp, but did not statistically reduce entrance into the inguinal and mesenteric lymph nodes [9]. Following firm adhesion to HEV, lymphocytes transmigrate through the endothelium and enter the parenchyma of lymph nodes or Peyer's patches.…”