Virus

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LETTER

doi:10.1038/nature11599

Resurrection of endogenous retroviruses in
antibody-deficient mice
George R. Young1, Urszula Eksmond1, Rosalba Salcedo2, Lena Alexopoulou3, Jonathan P. Stoye4 & George Kassiotis1

Tcra2/2 or Tcrd2/2 mice, lacking T-cell receptor (TCR)ab and
TCRcd T cells, respectively, showed low eMLV expression (Fig. 1f).
eMLV expression was similarly low in H2-A,E2/2mice (MGI allele

Rag1–/–
60%

102

100

104
103
102
101
100

Monocytes Neutrophils

Rag1–/–

101
100
100 101 102 103 104
83A25
Ctrl antibody

100

76%

24%

Liver

101

105

Lung

102

WT
Cell counts (%)

Dendritic
cells

Erythroid
cells

35%

51%

64%

WT

Rag1–/–

NK cells

50

0
100 101 102 103 104

83A25

h
g

105

Cellcounts (%)

104
103
102

Ighm–/–

Ighm–/– MD4

H2-A,E–/–

Tcra–/–

Tcrd–/–

WT

100

Rag1–/–

101

100

CD4+
T cells

CD8+
T cells

96%

B cells

95%

85%

50

0
100 101 102 103 104

WT

83A25
Ighm–/–

MD4

Spleen

107
106
105
104
103
102
101
100

Tlr7–/–

106

WT

Spleen

107

Myd88–/–

f

eMLV expression, relative toHprt

Empty channel

103

103

WT
Rag1–/–

106

e

Splenocytes
WT

104

107

Kidney

d

1.9

105

c

Muscle

0
Log2 fold change

WT
Rag1–/–

Ileum

–1.9

106

Colon

Emv2 env
Emv2 gag
Ccl17
Ear11
Mgl2
Gm10002
Ms4a4c
Klrb1b
Cd209d

Macrophages
107

Spleen

Rag1–/–

eMLV expression, relative to Hprt

b

Macrophages
WT

eMLVexpression, relative to Hprt

a

eMLV expression, relative to Hprt

The mammalian host has developed a long-standing symbiotic relationship with a considerable number of microbial species. These
include the microbiota on environmental surfaces, such as the
respiratory and gastrointestinal tracts1, and also endogenous retroviruses (ERVs), comprising a substantial fraction of the mammaliangenome2,3. The long-term consequences for the host of
interactions with these microbial species can range from mutualism to parasitism and are not always completely understood.
The potential effect of one microbial symbiont on another is even
less clear. Here we study the control of ERVs in the commonly used
C57BL/6 (B6) mouse strain, which lacks endogenous murine leukaemia viruses (MLVs) able toreplicate in murine cells. We demonstrate the spontaneous emergence of fully infectious ecotropic4
MLV in B6 mice with a range of distinct immune deficiencies
affecting antibody production. These recombinant retroviruses
establish infection of immunodeficient mouse colonies, and ultimately result in retrovirus-induced lymphomas. Notably, ERV
activation in immunodeficient mice is prevented inhusbandry
conditions associated with reduced or absent intestinal microbiota. Our results shed light onto a previously unappreciated role
for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a
range of pathologies associated with ERVs, including cancer.
Retroviruses can establish germline infection and become part of
thehost genome2,3. Most, if not all, ERVs have become inactive owing
to mutations, or transcriptionally silenced through the action of diverse
mechanisms2,3. However, RNA and protein expression of replicationdefective ERVs are frequently increased in infection, autoimmunity and
cancer2,3. Whether or not the immune system defends against potential
threats posed by ERVs is unclear. To address therole of adaptive immunity in this process, we assessed ERV expression in B6 mice. We
initially compared the transcriptional profiles of purified macrophages
from B6 wild-type and T- and B-cell-deficient Rag12/2 mice. The two
transcripts with the highest increase in expression levels in macrophages from Rag12/2 mice (Fig. 1a) correspond to the env and gag
genes, respectively (Supplementary...
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