Regulating the regulators of the immune system
Date:
April 19, 2022
Source:
University of Pennsylvania
Summary:
Scientists reveal a new layer of complexity with which the immune
system finds a balance between controlling pathogens and protecting
healthy tissue.
FULL STORY ========================================================================== Checkpoint inhibitors have become important tools in the cancer-fighting arsenal. By blocking proteins that normally restrain the immune response,
these drugs can help the immune system destroy cancer cells.
==========================================================================
But they don't work in all patients. And now a new study in Nature Immunologyled by researchers from Penn's School of Veterinary Medicine
suggests a possible reason why: Not only can these drugs encourage the
activity of cancer killing T cells, but they can, in some cases, also
activate a population of regulatory T cells that serve the opposing
function -- to rein in that attack.
In the study, immunologists led by Penn Vet professor Christopher Hunter
and doctoral student Joseph Perry discovered that blocking the activity
of the checkpoint protein PD-L1, which interacts with a T cell receptor
PD-1, enhanced the activity of a subset of T cells known as effector
regulatory T cells, or effector Tregs. This intervention unexpectedly
reduced the ability of mice to control a parasite infection.
The findings reveal a complexity to how the body "regulates the
regulators" of the immune system, says Hunter. "Once you have those
Tregs to control your T cell response, you also need to control them,"
he says. "It's like with a car.
You have the ignition, the accelerator, and you also need a brake. PD-1
is a brake not only on killer T cells but also on Tregs." T cells may
be best known for their roles in fighting infections and killing cancer
cells. But the immune system also has several mechanisms in place to counterbalance those responses to prevent out-of-control inflammation that could damage healthy tissue. Tregs are one aspect of this balancing act.
"You can think of Tregs as the health and safety inspectors of the immune system," Hunter says. "They're really important, but sometimes, when you
need to mount an immune response against a pathogen, you need them to take
a back seat. When an infection is present, we see Treg levels crash so
that an effector response can emerge. But we never understood what causes
that crash." The researchers began to understand more after exploring
an unanticipated finding. They discovered that, when the checkpoint
protein PD-L1 was blocked, mice infected with Toxoplasma gondii were
less effective at fighting off the parasite than mice with an uninhibited PD-L1. "That was the opposite of what we expected," Hunter says, as the
dogma would have suggested that blocking this checkpoint inhibitor would
allow for a better effector T cell response against infection.
========================================================================== Digging into the surprising result, Perry, Hunter, and colleagues
realized that it aligned with what some cancer researchers had recently reported. In certain cancers, the other groups had found, blocking PD-L1
led to worse outcomes, seemingly because of an increase in a population
of Tregs that restrained killing of cancer cells.
When the Penn-led team looked in the context of a T. gondii infection,
they discovered the signaling molecule interferon gamma turned on
PD-L1, which precipitated a rapid decline in Treg numbers. A PD-L1
inhibitor mitigated this effect and stopped the Treg crash. This
treatment alleviated the harmful effects of inflammation on mice but
also impaired the ability of T cells to fight infection. Similarly,
Tregs altered to lack PD-1, the receptor which with PD-L1 interacts,
also led to increases in Treg activity.
"It seems that the effector T cell versus Treg ratio is really important,"
says Hunter.
As the researchers began to learn more about how Tregs were activated
and operated during an infection, they were curious about whether this
pathway worked when animals were in a normal, healthy state. Just as
there are different types of "regular" T cells, including CD8 and CD4 T
cells and many more subdivisions besides, the new work underscores that
there are subpopulations of Tregs as well, which have different roles
in the body. In healthy, uninfected animals, the team found differences
between the proteins expressed by different Treg populations, including
some that expressed PD-1, which the researchers termed "effector Tregs."
"These results taught us that there's a large population of activated
PD-1- positive Treg cells present as a normal part of everyday life that
help limit the immune system," Perry says.
==========================================================================
"We think these PD-1 high cells are the most active Tregs," says
Hunter. "It's a complex landscape, and it's possible that some checkpoint inhibitor treatments have been inadvertently targeting these Tregs and
not others, leading to unexpected outcomes." In ongoing investigations, Hunter, Perry, and colleagues continue to examine this pathway, as
well as those involved in other immune checkpoints. The findings could
have implications not only in refining cancer checkpoint inhibitor
therapies but also in conceiving new strategies for treating autoimmune disease. "In that case you would want to increase the number of Tregs,"
Hunter says. "Maybe we could think about ways to augment that arm of the
immune system to treat inflammatory diseases." Christopher A. Hunter
is the Mindy Halikman Heyer Distinguished Professor of Pathobiology at
the University of Pennsylvania School of Veterinary Medicine.
Hunter's coauthors are Penn Vet's Joseph A. Perry, Lindsey Shallberg,
Joseph T.
Clark, Jodie Gullicksrud, Jonathan H. DeLong, Bonnie B. Douglas, Zachary Lanzar, Keenan O'Dea, Christoph Konradt, Jeongho Park, Daniel Grubaugh,
Arielle Glatman Zaretsky, Igor E. Brodsky, and David A. Christian;
Penn's Perelman School of Medicine's Andrew P. Hart; Merck & Co.'s Renee
de Waal Malefyt; and Harvard Medical School's Juhi R. Kuchroo and Arlene
H. Sharpe.
The study was supported by the National Institute of Allergy and
Infectious Diseases (grants AI125563 and AI41158).
========================================================================== Story Source: Materials provided by University_of_Pennsylvania. Note:
Content may be edited for style and length.
========================================================================== Journal Reference:
1. Joseph A. Perry, Lindsey Shallberg, Joseph T. Clark, Jodi
A. Gullicksrud,
Jonathan H. DeLong, Bonnie B. Douglas, Andrew P. Hart, Zachary
Lanzar, Keenan O'Dea, Christoph Konradt, Jeongho Park, Juhi
R. Kuchroo, Daniel Grubaugh, Arielle Glatman Zaretsky, Igor
E. Brodsky, Rene de Waal Malefyt, David A. Christian, Arlene
H. Sharpe, Christopher A. Hunter. PD- L1-PD-1 interactions limit
effector regulatory T cell populations at homeostasis and during
infection. Nature Immunology, 2022; DOI: 10.1038/ s41590-022-01170-w ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/04/220419170749.htm
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