title: Loss of Kindlin-3 in LAD-III eliminates LFA-1 but not VLA-4 adhesiveness developed under shear flow conditions.
abstract: Leukocyte adhesion deficiency (LAD)-III is associated with homozygous stop codon mutations in Kindlin-3, the hematopoietic member of the Kindlin family of integrin coactivators. In addition, a subgroup of LAD-III patients has a homozygous splice junction mutation in and reduced expression of the Rap-1 guanine nucleotide exchange factor, CalDAG-GEFI (CDGI). In this study, we compared the adhesive properties of the leukocyte function-associated antigen-1 (LFA-1) and very late activation antigen-4 (VLA-4) integrins in both primary and activated leukocytes derived from these 2 LAD-III subgroups. Primary lymphocytes lacking both Kindlin-3 and CDGI lost all firm T-cell receptor-stimulated LFA-1 adhesiveness, in contrast to LAD-III lymphocytes deficient in Kindlin-3 alone. Effector T cells expanded from all tested LAD-III variants expressed normal CDGI, but lacked Kindlin-3. These Kindlin-3-null effector T cells exhibited total loss of inside-out LFA-1 activation by chemokine signals as well as abrogated intrinsic LFA-1 adhesiveness. Surprisingly, VLA-4 in Kindlin-3-null resting or effector lymphocytes retained intrinsic rolling adhesions to vascular cell adhesion molecule-1 and exhibited only partial defects in chemokine-stimulated adhesiveness to vascular cell adhesion molecule-1. Deletion of the putative beta(1) Kindlin-3 binding site also retained VLA-4 adhesiveness. Thus, our study provides the first evidence that Kindlin-3 is more critical to LFA-1 than to VLA-4-adhesive functions in human lymphocytes.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Manevich-Mendelson
authors.forename: Sara W
authors.initials: SW
authors.lastname: Feigelson
authors.forename: Ronit
authors.initials: R
authors.lastname: Pasvolsky
authors.forename: Memet
authors.initials: M
authors.lastname: Aker
authors.forename: Valentin
authors.initials: V
authors.lastname: Grabovsky
authors.forename: Ziv
authors.initials: Z
authors.lastname: Shulman
authors.forename: Sara Sebnem
authors.initials: SS
authors.lastname: Kilic
authors.forename: Maria Alessandra
authors.initials: MA
authors.lastname: Rosenthal-Allieri
authors.forename: Shifra
authors.initials: S
authors.lastname: Ben-Dor
authors.forename: Adi
authors.initials: A
authors.lastname: Mory
authors.forename: Alain
authors.initials: A
authors.lastname: Bernard
authors.forename: Markus
authors.initials: M
authors.lastname: Moser
authors.forename: Amos
authors.initials: A
authors.lastname: Etzioni
authors.forename: Ronen
authors.initials: R
authors.lastname: Alon
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D018388:Codon, Terminator / Q000235:genetics; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000378:metabolism*; D036904:Leukocyte Rolling; D018370:Leukocyte-Adhesion Deficiency Syndrome / Q000235:genetics / Q000378:metabolism*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D022821:RNA Splice Sites / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018388:Codon, Terminator; C477322:FERMT3 protein, human; D020662:Guanine Nucleotide Exchange Factors; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C115955:RAP1GDS1 protein, human; D022821:RNA Splice Sites; D019010:Vascular Cell Adhesion Molecule-1