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Subunit 1 of the Prefoldin Chaperone Complex Is Required for Lymphocyte Development and Function¹

Department of Microbiology and Immunology, Vanderbilt University, School of Medicine, Nashville, TN 37232

Prefoldin is a hexameric chaperone that facilitates posttranslational folding of actins and other cytoskeletal proteins by the Tcp1-containing ring complex chaperonin, TriC. The present study characterized mice with a null mutation in Pfdn1, which encodes the first subunit of the Prefoldin complex. Pfdn1-deficient mice displayed phenotypes characteristic of defects in cytoskeletal function, including manifestations of ciliary dyskinesia, neuronal loss, and defects in B and T cell development and function. B and T cell maturation was markedly impaired at relatively early stages, namely at the transitions from pre-pro-B to pre-B cells in the bone marrow and from CD4^–CD8^– double-negative to CD4⁺CD8⁺ double-positive T cells in the thymus. In addition, mature B and T lymphocytes displayed cell activation defects upon Ag receptor cross-linking accompanied by impaired Ag receptor capping in B cells. These phenotypes illustrate the importance of cytoskeletal function in immune cell development and activation.

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¹ This work was supported by Public Health Service Grants P01HL68744 (to H.E.R.) and AI060729-01 (to W.N.K.). K.L.H. was supported by National Institutes of Health Grant F32-AI069770-01. Additional support was provided by the Department of Microbiology and Immunology of Vanderbilt University and by Cancer Center Support Grant P30CA68485 to the Vanderbilt-Ingram Cancer Center.

² S.C. and G.C. share first authorship and contributed equally to this work.

³ Current address: MedImmune, Inc., One MedImmune Way, Department of Inflammation and Autoimmunity, Gaithersburg, MD 20878

⁴ Address correspondence and reprint requests to Dr. Wasif N. Khan and Dr. H. Earl Ruley, Department of Microbiology and Immunology, Vanderbilt University, School of Medicine, Medical Center North, 1161 21st Avenue South, Nashville, TN 37232. E-mail addresses: wasif.khan{at}Vanderbilt.edu and earl.ruley{at}vanderbilt.edu

⁵ Abbreviations used in this paper: ES, embryonic stem; BM, bone marrow; MEF, mouse embryonic fibroblast; MZ, marginal zone; WASP, Wiskott-Aldrich syndrome protein; WIP, WASP-interacting protein; MFI, mean fluorescent intensity.