title: Narrowed TCR repertoire and viral escape as a consequence of heterologous immunity.
abstract: Why some virus-specific CD8 TCR repertoires are diverse and others restricted or "oligoclonal" has been unknown. We show here that oligoclonality and extreme clonal dominance can be a consequence of T cell cross-reactivity. Lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV) encode NP(205-212) epitopes that induce different but highly cross-reactive diverse TCR repertoires. Homologous viral challenge of immune mice only slightly skewed the repertoire and enriched for predictable TCR motifs. However, heterologous viral challenge resulted in a narrow oligoclonal repertoire with dominant clones with unpredictable TCR sequences. This shift in clonal dominance varied with the private, i.e., unique, specificity of the host's TCR repertoire and was simulated using affinity-based computer models. The skewing differences in TCR repertoire following homologous versus heterologous challenge were observed within the same private immune system in mice adoptively reconstituted with memory CD8 T cell pools from the same donor. Conditions driving oligoclonality resulted in an LCMV epitope escape variant in vivo resembling the natural Lassa virus sequence. Thus, T cell oligoclonality, including extremes in clonal dominance, may be a consequence of heterologous immunity and lead to viral escape. This has implications for the design of peptide-based vaccines, which might unintentionally prime for skewed TCR responses to cross-reactive epitopes.
authors.affiliation: Department of Pathology and Program in Immunology and Virology, University of Massachusetts Medical School (UMMS), Worcester, Massachusetts 01655, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Cornberg
authors.forename: Alex T
authors.initials: AT
authors.lastname: Chen
authors.forename: Lee A
authors.initials: LA
authors.lastname: Wilkinson
authors.forename: Michael A
authors.initials: MA
authors.lastname: Brehm
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Kim
authors.forename: Claudia
authors.initials: C
authors.lastname: Calcagno
authors.forename: Dario
authors.initials: D
authors.lastname: Ghersi
authors.forename: Roberto
authors.initials: R
authors.lastname: Puzone
authors.forename: Franco
authors.initials: F
authors.lastname: Celada
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.forename: Liisa K
authors.initials: LK
authors.lastname: Selin
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D006224:Cricetinae; D000939:Epitopes / Q000737:chemistry; D007107:Immune System / Q000502:physiology; D007156:Immunologic Memory; D008217:Lymphocytic choriomeningitis virus / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000737:chemistry; D018052:Pichinde virus / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*
chemical_list: D000939:Epitopes; D010455:Peptides; D011948:Receptors, Antigen, T-Cell