Abstract
Kaposi sarcoma herpesvirus (KSHV/HHV-8) is a B cell tropic human pathogen, which is present in vivo in monotypic immunoglobulin λ (Igλ) light chain but polyclonal B cells. In the current study, we use cell sorting to infect specific B cell lineages from human tonsil specimens in order to examine the immunophenotypic alterations associated with KSHV infection. We describe IL-6 dependent maturation of naïve B lymphocytes in response to KSHV infection and determine that the Igλ monotypic bias of KSHV infection in vivo is due to viral induction of BCR revision. Infection of immunoglobulin κ (Igκ) naïve B cells induces expression of Igλ and isotypic inclusion, with eventual loss of Igκ. We show that this phenotypic shift occurs via re-induction of Rag-mediated V(D)J recombination. These data explain the selective presence of KSHV in Igλ B cells in vivo and provide the first evidence that a human pathogen can manipulate the molecular mechanisms responsible for immunoglobulin diversity.
Highlights
Kaposi sarcoma herpesvirus (KSHV), called human herpesvirus 8 (HHV-8) is the most recently discovered human herpesvirus, and infection with this virus is linked to the development of KSHV-associated malignancy including Kaposi sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD), in the absence of adequate immune surveillance (e.g. HIV disease). [1,2,3,4]
We develop a novel system for infecting B cells from human tonsil with KSHV and tracking how the virus alters the cells over time
We demonstrate a number of KSHV-driven alterations in B cells, including the fact that KSHV infection of kappa light chain positive B cells drives them to become lambda light chain positive by re-inducing recombination events that are normally restricted to B cell development in the bone marrow
Summary
Kaposi sarcoma herpesvirus (KSHV), called human herpesvirus 8 (HHV-8) is the most recently discovered human herpesvirus, and infection with this virus is linked to the development of KSHV-associated malignancy including Kaposi sarcoma, primary effusion lymphoma (PEL) and multicentric Castleman disease (MCD), in the absence of adequate immune surveillance (e.g. HIV disease). [1,2,3,4]. During B lymphocyte development, establishment of tolerance in the bone marrow involves the sequential production of immunoglobulin light chain rearrangements by V(D)J-recombination orchestrated by the lymphoid lineage-specific recombinase activating gene (RAG) protein products, Rag and Rag2[10]. This phenomenon, termed B cell receptor (BCR) editing begins with rearrangements of the immunoglobulin κ (Igκ) locus, and rearrangements in the immunoglobulin λ (Igλ) locus occur only when Igκ rearrangements fail to produce a functional, non-autoreactive BCR. Infection of total tonsil-derived B lymphocytes in vitro with KSHV has shown that infected cells are biased towards Igλ+ cells[9]. The restriction of KSHV infection to Igλ+ lymphocytes remains a conundrum in the field
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
