Regulation of α4β7 on naïve T cells upon viral infection

The elimination of virus-infected cells to block viral spread is
substantially conveyed by effector CD8+ T cells. Trafficking of
naïve T cells into the lymph node is a crucial step for their
activation to effector T cells. The entry into the lymph nodes is
mediated by several cell adhesion molecules that are highly
specific for given lymph nodes. For the ingress into the
gut-associated lymphoid tissue (GALT) such as mesenteric lymph
nodes and Peyer’s patches, the integrin α4β7 is the major homing
receptor that interacts with its main ligand MAdCAM-1. On naïve T
cells, α4β7 is expressed at low level, however upon activation in
the GALT its expression is significantly upregulated on effector T
cells. Consequently these effector T cells migrate into the
gastrointestinal tract, where MAdCAM-1 is also expressed. The
migration patterns of virus-specific CD8+ T cells upon viral
infection have been studied in detail. In contrast, the migration
of the major population of virus-unspecific CD8+ T cells, i.e.
bystander-activated T cells is poorly understood. In our study, we
aimed to determine how trafficking of these non-cognate,
bystander-activated T cells is affected upon viral infection. We
discovered that α4β7 expression was negatively regulated on
bystander-activated CD8+ T cells upon injection of poly (I:C),
which imitates innate immune activation upon viral infection. This
effect was also observed for viral infections such as Sendai, EMCV
and the mutant form of VSV virus. Furthermore, we scrutinized the
direct role of IFN-α on T cells to exert α4β7 modulation. In the
case of EMCV infection, IL-6 played a dominant role in the
alteration of α4β7 expression. Finally, using an adoptive transfer
model we could prove that the downregulation severely impacted the
trafficking of T cells into the Peyer’s patches and to a lesser
extent into the mesenteric lymph nodes. These findings demonstrate
that a mechanism to regulate trafficking of bystander-activated T
cells during viral infection exists and that this is controlled by
the induction of cytokines such as IFN-α and IL-6. We hypothesize
that the downregulation of α4β7 on naïve T cells functions 1) to
allow space for virus-specific effector T cells to expand in the
GALT and 2) to exclude bystander-activated T cells from the GALT in
order to prevent mistrafficking, which could cause autoimmune
diseases.