Severity of Acute Infectious Mononucleosis Correlates with Cross-Reactive Influenza CD8 T-Cell Receptor Repertoires

Abstract

Fifty years after the discovery of Epstein-Barr virus (EBV), it remains unclear how primary infection with this virus leads to massive CD8 T-cell expansion and acute infectious mononucleosis (AIM) in young adults. AIM can vary greatly in severity, from a mild transient influenza-like illness to a prolonged severe syndrome. We questioned whether expansion of a unique HLA-A2.01-restricted, cross-reactive CD8 T-cell response between influenza virus A-M158 (IAV-M1) and EBV BMLF1280 (EBV-BM) could modulate the immune response to EBV and play a role in determining the severity of AIM in 32 college students. Only ex vivo total IAV-M1 and IAV-M1+EBV-BM cross-reactive tetramer+ frequencies directly correlated with AIM severity and were predictive of severe disease. Expansion of specific cross-reactive memory IAV-M1 T-cell receptor (TCR) Vβ repertoires correlated with levels of disease severity. There were unique profiles of qualitatively different functional responses in the cross-reactive and EBV-specific CD8 T-cell responses in each of the three groups studied, severe-AIM patients, mild-AIM patients, and seropositive persistently EBV-infected healthy donors, that may result from differences in TCR repertoire use. IAV-M1 tetramer+ cells were functionally cross-reactive in short-term cultures, were associated with the highest disease severity in AIM, and displayed enhanced production of gamma interferon, a cytokine that greatly amplifies immune responses, thus frequently contributing to induction of immunopathology. Altogether, these data link heterologous immunity via CD8 T-cell cross-reactivity to CD8 T-cell repertoire selection, function, and resultant disease severity in a common and important human infection. In particular, it highlights for the first time a direct link between the TCR repertoire with pathogenesis and the diversity of outcomes upon pathogen encounter.

Antigen‐specific CD8 T cells in cell cycle circulate in the blood after vaccination

“…Remarkably, we found a twofold‐sixfold greater proportion of gag‐specific CD8 T cells in the “relaxed” gate population than in the “narrow” gate population in both LNs and spleen (Figure D‐E). Although this gating strategy is novel for standard ex vivo studies of lymphocytes (Figure A‐B, “narrow” gate at step 3), cells with high FSC‐A and high SSC‐A are often included when examining in vitro activated T cells . Notably, in current ex vivo studies of lymphocytes, single cells are normally excluded in the FSC‐A/FSC‐H gate (Figure A‐B) and less frequently by a two‐step gating strategy using FSC‐H/FSC‐W and SSC‐H/SSC‐W plots.…”

Respiratory virus-induced heterologous immunity

“…Reactivation of IV-M158specific CD8 + T cells, which are cross-reactive to the EBV BamHI M fragment leftward open reading frame 1280-288 (BMLF1280) epitope were shown to contribute to lymphoproliferation in IM ( [48]; Table 1). In addition, frequency of IV-M158 and M158-EBV BMLF1280 tetramer + CD8 + T cells correlated with IM disease severity [83]. This was associated with different TCR repertoire usage and enhanced IFNγ production.…”

Respiratory virus-induced heterologous immunity

“…1). In addition, frequency of IV-M1 58 and M1 58 -EBV BMLF1 280 tetramer + CD8 + T cells correlated with IM disease severity [83]. is was associated with di erent TCR repertoire usage and enhanced IFNγ production.…”

“…A larger cohort study with 175 HIV seropositive HLA-A2 + subjects con rmed HIV-1 and IV cross-reactivity. T cells of HIV + individuals frequently targeted the p17 GAG [77][78][79][80][81][82][83][84][85] and the IV-M1 58 epitopes in vitro [51]. About 40 % showed T cells speci c for both epitopes in vitro [51].…”