Epstein-Barr Virus LMP2A Reduces Hyperactivation Induced by LMP1 to Restore Normal B Cell Phenotype in Transgenic Mice

Epstein-Barr virus (EBV) latently infects most of the human population and is strongly associated with lymphoproliferative disorders. EBV encodes several latency proteins affecting B cell proliferation and survival, including latent membrane protein 2A (LMP2A) and the EBV oncoprotein LMP1. LMP1 and LMP2A signaling mimics CD40 and BCR signaling, respectively, and has been proposed to alter B cell functions including the ability of latently-infected B cells to access and transit the germinal center. In addition, several studies suggested a role for LMP2A modulation of LMP1 signaling in cell lines by alteration of TRAFs, signaling molecules used by LMP1. In this study, we investigated whether LMP1 and LMP2A co-expression in a transgenic mouse model alters B cell maturation and the response to antigen, and whether LMP2A modulates LMP1 function. Naïve LMP1/2A mice had similar lymphocyte populations and antibody production by flow cytometry and ELISA compared to controls. In the response to antigen, LMP2A expression in LMP1/2A animals rescued the impairment in germinal center generation promoted by LMP1. LMP1/2A animals produced high-affinity, class-switched antibody and plasma cells at levels similar to controls. In vitro, LMP1 upregulated activation markers and promoted B cell hyperproliferation, and co-expression of LMP2A restored a wild-type phenotype. By RT-PCR and immunoblot, LMP1 B cells demonstrated TRAF2 levels four-fold higher than non-transgenic controls, and co-expression of LMP2A restored TRAF2 levels to wild-type levels. No difference in TRAF3 levels was detected. While modulation of other TRAF family members remains to be assessed, normalization of the LMP1-induced B cell phenotype through LMP2A modulation of TRAF2 may be a pathway by which LMP2A controls B cell function. These findings identify an advance in the understanding of how Epstein-Barr virus can access the germinal center in vivo, a site critical for both the genesis of immunological memory and of virus-associated tumors

Non-perturbative renormalization of quark bilinear operators with Nf=2 (tmQCD) Wilson fermions and the tree-level improved gauge action

We present results for the renormalization constants of bilinear quark operators obtained by using the tree-level Symanzik improved gauge action and the Nf=2 twisted mass fermion action at maximal twist, which guarantees automatic O(a)-improvement. Our results are also relevant for the corresponding standard (un-twisted) Wilson fermionic action since the two actions only differ, in the massless limit, by a chiral rotation of the quark fields. The scale-independent renormalization constants ZV, ZA and the ratio ZP/ZS have been computed using the RI-MOM approach, as well as other alternative methods. For ZA and ZP/ZS, the latter are based on both standard twisted mass and Osterwalder-Seiler fermions, while for ZV a Ward Identity has been used. The quark field renormalization constant Zq and the scale dependent renormalization constants ZS, ZP and ZT are determined in the RI-MOM scheme. Leading discretization effects of O(g^2 a^2), evaluated in one-loop perturbation theory, are explicitly subtracted from the RI-MOM estimates.Comment: 31 pages, 11 figure