title: Cross-reactive influenza virus-specific CD8+ T cells contribute to lymphoproliferation in Epstein-Barr virus-associated infectious mononucleosis.
abstract: The marked proliferation of activated CD8+ T cells is pathognomonic of EBV-associated infectious mononucleosis (IM), common in young adults. Since the diversity and size of the memory CD8+ T cell population increase with age, we questioned whether IM was mediated by the reactivation of memory CD8+ T cells specific to previously encountered pathogens but cross-reactive with EBV. Of 8 HLA-A2+ IM patients, 5 had activated T cells specific to another common virus, as evidenced by a significantly higher number of peripheral blood influenza A virus M1(58-66)-specific T cells compared with healthy immune donors. Two patients with an augmented M1 response had tetramer-defined cross-reactive cells recognizing influenza M1 and EBV-BMLF1(280-288), which accounted for up to one-third of their BMLF1-specific population and likely contributed to a skewed M1-specific T cell receptor repertoire. These epitopes, with only 33% sequence similarity, mediated differential effects on the function of the cross-reactive T cells, which may contribute to alterations in disease outcome. EBV could potentially encode an extensive pool of T cell epitopes that activate other cross-reactive memory T cells. Our results support the concept that cross-reactive memory CD8+ T cells activated by EBV contribute to the characteristic lymphoproliferation of IM.
authors.affiliation: Department of Pathology, Program in Immunology and Virology, University of Massachusetts Medical School, Worcester, Massachusetts 01655, USA.
authors.forename: Shalyn C
authors.initials: SC
authors.lastname: Clute
authors.forename: Levi B
authors.initials: LB
authors.lastname: Watkin
authors.forename: Markus
authors.initials: M
authors.lastname: Cornberg
authors.forename: Yuri N
authors.initials: YN
authors.lastname: Naumov
authors.forename: John L
authors.initials: JL
authors.lastname: Sullivan
authors.forename: Katherine
authors.initials: K
authors.lastname: Luzuriaga
authors.forename: Raymond M
authors.initials: RM
authors.lastname: Welsh
authors.forename: Liisa K
authors.initials: LK
authors.lastname: Selin
mesh_terms: D000293:Adolescent; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism / Q000821:virology*; D049109:Cell Proliferation; D054407:Chemokine CCL4; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D005434:Flow Cytometry; D005805:Genes, MHC Class I; D015789:HLA-A2 Antigen / Q000737:chemistry; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D007244:Infectious Mononucleosis / Q000821:virology*; D009980:Influenza A virus / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020014:K562 Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology* / Q000821:virology*; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D009975:Orthomyxoviridae / Q000235:genetics*; D010455:Peptides / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000821:virology; D013997:Time Factors
chemical_list: D054407:Chemokine CCL4; D000939:Epitopes; D015789:HLA-A2 Antigen; D019402:Macrophage Inflammatory Proteins; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma