Attenuated immune control of Epstein-Barr virus in humanized mice is associated with the multiple sclerosis risk factor HLA-DR15

Eur J Immunol. 2021 Jan;51(1):64-75. doi: 10.1002/eji.202048655. Epub 2020 Nov 3.


Immune responses to Epstein-Barr virus (EBV) infection synergize with the main genetic risk factor HLA-DRB1*15:01 (HLA-DR15) to increase the likelihood to develop the autoimmune disease multiple sclerosis (MS) at least sevenfold. In order to gain insights into this synergy, we investigated HLA-DR15 positive human immune compartments after reconstitution in immune-compromised mice (humanized mice) with and without EBV infection. We detected elevated activation of both CD4+ and CD8+ T cells in HLA-DR15 donor-reconstituted humanized mice at steady state, even when compared to immune compartments carrying HLA-DRB1*04:01 (HLA-DR4), which is associated with other autoimmune diseases. Increased CD8+ T cell expansion and activation was also observed in HLA-DR15 donor-reconstituted humanized mice after EBV infection. Despite this higher immune activation, EBV viral loads were less well controlled in the context of HLA-DR15. Indeed, HLA-DR15-restricted CD4+ T cell clones recognized EBV-transformed B cell lines less efficiently and demonstrated cross-reactivity toward allogeneic target cells and one MS autoantigen. These findings suggest that EBV as one of the main environmental risk factors and HLA-DR15 as the main genetic risk factor for MS synergize by priming hyperreactive T-cell compartments, which then control the viral infection less efficiently and contain cross-reactive CD4+ T cell clones.

Keywords: Epstein-Barr virus; HLA-DR; T cells; autoimmunity; multiple sclerosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Cross Reactions
  • Disease Models, Animal
  • Epstein-Barr Virus Infections / complications
  • Epstein-Barr Virus Infections / immunology*
  • Epstein-Barr Virus Infections / virology
  • Genetic Predisposition to Disease
  • HLA-A2 Antigen / genetics
  • HLA-A2 Antigen / immunology
  • HLA-DR Serological Subtypes / genetics
  • HLA-DR Serological Subtypes / immunology*
  • Herpesvirus 4, Human / immunology
  • Humans
  • Isoantigens
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mice, Transgenic
  • Multiple Sclerosis / etiology
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Myelin Sheath / immunology
  • Risk Factors


  • HLA-A2 Antigen
  • HLA-DR Serological Subtypes
  • HLA-DR15 antigen
  • Isoantigens