title: PI3K p110δ is expressed by gp38(-)CD31(+) and gp38(+)CD31(+) spleen stromal cells and regulates their CCL19, CCL21, and LTβR mRNA levels.
abstract: The role of p110δ PI3K in lymphoid cells has been studied extensively, showing its importance in immune cell differentiation, activation and development. Altered T cell localization in p110δ-deficient mouse spleen suggested a role for p110δ in non-hematopoietic stromal cells, which maintain hematopoietic cell segregation. We tested this hypothesis using p110δ(WT/WT) mouse bone marrow to reconstitute lethally irradiated p110δ(WT/WT) or p110δ(D910A/D910A) (which express catalytically inactive p110δ) recipients, and studied localization, number and percentage of hematopoietic cell subsets in spleen and lymph nodes, in homeostatic conditions and after antigen stimulation. These analyses showed diffuse T cell areas in p110δ(D910A/D910A) and in reconstituted p110δ(D910A/D910A) mice in homeostatic conditions. In these mice, spleen CD4(+) and CD8(+) T cell numbers did not increase in response to antigen, suggesting that a p110δ(D910A/D910A) stroma defect impedes correct T cell response. FACS analysis of spleen stromal cell populations showed a decrease in the percentage of gp38(-)CD31(+) cells in p110δ(D910A/D910A) mice. qRT-PCR studies detected p110δ mRNA expression in p110δ(WT/WT) spleen gp38(-)CD31(+) and gp38(+)CD31(+) subsets, which was reduced in p110δ(D910A/D910A) spleen. Lack of p110δ activity in these cell populations correlated with lower LTβR, CCL19 and CCL21 mRNA levels; these molecules participate in T cell localization to specific spleen areas. Our results could explain the lower T cell numbers and more diffuse T cell areas found in p110δ(D910A/D910A) mouse spleen, as well as the lower T cell expansion after antigen stimulation in p110δ(D910A/D910A) compared with p110δ(WT/WT) mice.
authors.affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas, Madrid, Spain.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Zotes
authors.forename: Roberto
authors.initials: R
authors.lastname: Spada
authors.forename: Vladimir
authors.initials: V
authors.lastname: Mulens
authors.forename: Sonia
authors.initials: S
authors.lastname: Pérez-Yagüe
authors.forename: Carlos O
authors.initials: CO
authors.lastname: Sorzano
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Ana C
authors.initials: AC
authors.lastname: Carrera
authors.forename: Domingo F
authors.initials: DF
authors.lastname: Barber
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology; D054415:Chemokine CCL19 / Q000235:genetics* / Q000378:metabolism; D054421:Chemokine CCL21 / Q000235:genetics* / Q000378:metabolism; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D016130:Immunophenotyping; D008221:Lymphoid Tissue / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000235:genetics / Q000378:metabolism; D000098853:Podoplanin
chemical_list: D000941:Antigens; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D058543:Class Ia Phosphatidylinositol 3-Kinase; D053259:Lymphotoxin beta Receptor; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D048069:Tumor Necrosis Factors; C490441:Pdpn protein, mouse; D000098853:Podoplanin