Stability and Diversity of  T Cell Receptor Repertoire Usage during Lymphocytic Choriomeningitis Virus Infection of Mice

Abstract

Numerous studies have examined T cell receptor (TCR) usage of selected virus-specific T cell clones, yet little information is available regarding the stability and diversity of TCR repertoire usage during viral infections. Here, we analyzed the Vβ8.1 TCR repertoire directly ex vivo by complementarity-determining region 3 (CDR3) length spectratyping throughout the acute lymphocytic choriomeningitis virus (LCMV) infection, into memory, and under conditions of T cell clonal exhaustion. The Vβ8 population represented 30–35% of the LCMV-induced CD8+ T cells and included T cells recognizing several LCMV-encoded peptides, allowing for a comprehensive study of a multiclonal T cell response against a complex antigen. Genetically identical mice generated remarkably different T cell responses, as reflected by different spectratypes and different TCR sequences in same sized spectratype bands; however, a conserved CDR3 motif was found within some same sized bands. This indicated that meaningful studies on the evolution of the T cell repertoire required longitudinal studies within individual mice. Such longitudinal studies with peripheral blood lymphocyte samples showed that (a) the virus-induced T cell repertoire changes little during the apoptosis period after clearance of the viral antigens; (b) the LCMV infection dramatically skews the host T cell repertoire in the memory state; and (c) continuous selection of the T cell repertoire occurs under conditions of persistent infections.

Preferential Escape of Subdominant CD8+ T Cells During Negative Selection Results in an Altered Antiviral T Cell Hierarchy

“…6A). Although NP118-specific T cells from RIP-NP mice demonstrated a slight increase in their frequency of new V␤ families such as V␤4 and V␤6, the dominant V␤ families still consisted mainly of V␤8.1/8.2 and V␤10, similar to that observed in BALB/c mice (16,34).…”

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

“…It has also been proposed that successive and repetitive stimulation upon chronic infection might be responsible for TCR repertoire narrowing (14,15). However, the idea of repertoire narrowing is not consensual either in experimental models or during HIV infection (16)(17)(18). In addition, it has been shown that the TCR repertoire directed against a particular CMV-derived epitope remained quite heterogeneous in healthy individuals (15).…”

Direct Ex Vivo Kinetic and Phenotypic Analyses of CD8+T-Cell Responses Induced by DNA Immunization

“…In addition, these cells are an important component of the immunity conferred by attenuated and recombinant viruses and by plasmid DNA vaccines. Although the kinetics of the antiviral CD8 ϩ T-cell response during the inductive and memory phases of certain systemic viral infections have been well characterized (8,16,19), there is little detailed knowledge about the kinetics of cellular immunity induced by conventional vaccines or by DNA immunization. Of particular interest is how rapidly CD8 ϩ T-cell responses develop after vaccination, as these cells play a critical role in limiting virus replication.…”