Murine γ-herpesvirus infection causes Vβ4-specific CDR3-restricted clonal expansions within CD8+ peripheral blood T lymphocytes

Abstract

Infection of mice with the γ-herpesvirus MHV-68 results in lytic infection in the lung cleared by CD8⁺ cells and establishment of lifelong latency. An Epstein–Barr virus (EBV)-like infectious mononucleosis (IM) syndrome emerges ~3 weeks after infection. In human IM, the majority of T cells in the peripheral blood are monoclonal or oligoclonal and are frequently specific for lytic or latent viral epitopes. However, a unique feature of MHV-68-induced IM is a prominent MHC haplotype-independent expansion of CD8⁺ T cells, the majority of which utilize V_β4 chains in their αβTCR. The ligand driving the V_β4 expansion is unknown, but the V_β bias and MHC haplotype independence raised the possibility that these cells were responding to a virally encoded or a virally induced endogenous superantigen (sAg). The aim of this study was to determine whether this rapidly proliferating subset is composed of polyclonally or clonally expanded T cells. Complementarity-determining region (CDR)-3 size analysis of V_β4⁺CD8⁺ cells in infected mice demonstrated CDR3-restricted expansions in the V_β4 family as a whole. More refined analysis demonstrated major distortions in every J_β subfamily. V–D–J junctional region sequencing indicated that these CDR3 size-restricted expansions were composed of clonal or oligoclonal populations. The sequences were largely unique in individual mice, although evidence for `public' or highly conserved T cell expansions was also seen between different mice. Taken together with previous studies showing an apparent MHC independence, the data suggest that a novel ligand, distinct from conventional sAg and peptide–MHC, drives proliferation of V_β4⁺CD8⁺ T cells.