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Research published in The Journal of Clinical Investigation provides new insights regarding CD8 regulatory T cells (Tregs).
Investigators found that, in young, healthy individuals, CD8 Tregs suppress the activation and expansion of CD4 T cells.
However, older individuals and patients with a rare form of vasculitis exhibit CD8 Treg dysfunction, which is tied to a drop in production of an enzyme called NADPH oxidase 2 (NOX2).
Cornelia Weyand, MD, of Stanford University Medical Center in California, and her colleagues conducted this research.
First, the team found that CD8 Tregs preferentially take up residence in lymph nodes, the spleen, and other regions where there are huge “armies” of CD4 T cells. This proximity puts the CD8 Tregs in a position to stamp out CD4 T-cell activation early on.
Further experiments demonstrated that CD8 Tregs manufacture copious amounts of NOX2, which they package into tiny membrane-bound packets and transfer to the surfaces of abutting CD4 T cells.
These NOX2-laden packets are then taken up by the CD4 T cells. Inside their new home, the enzymes produce large volumes of highly reactive signaling substances that dial down CD4 T cells’ activation and proliferation.
The investigators noted that contact between CD8 Tregs and CD4 T cells in the early stages of activation shuts down the CD4 T cells’ activity and reduces their proliferation by half or more, even several days after the CD8 Tregs have been removed. Transferring NOX2 alone onto activated CD4 T cells also produces this effect.
Next, the team analyzed blood samples from healthy individuals and observed that CD8 Tregs were only about half as common in blood from people age 60 and older as in blood from 20- to 30-year-olds.
Both CD8 Treg numbers and their ability to suppress CD4 T-cell proliferation declined with advancing age. Experiments traced this to a drop in NOX2 production by older donors’ CD8 Tregs.
The investigators also discovered CD8 Treg failure in giant-cell arteritis (GCA). The team compared blood from GCA patients to blood from age-matched healthy control subjects and from patients with 2 other autoimmune diseases—psoriatic arthritis and small-vessel vasculitis. This revealed a severe deficit among GCA patients in NOX2-producing CD8 Tregs.
“This tells us that the deficit in NOX2-producing CD8 Tregs is specific to GCA, not just driving or driven by inflammation,” Dr Weyand said. “That’s good news for our patients who have this disease, which has been an enigma. Now we know something about what’s causing it.”
The discovery of NOX2 on the surface of CD8 Tregs—but not on other T-cell types—makes them much easier to identify and count, Dr Weyand added.
She and her colleagues are taking advantage of the new-found biomarker to tally CD8 Tregs in patients with age-associated disorders now understood to be driven by chronic inflammation to see if CD8 Treg deficits underlie some of these conditions’ pathology and whether they may be amenable to potential NOX2-restoring treatments. 
Image by Kathryn T. Iacono
Research published in The Journal of Clinical Investigation provides new insights regarding CD8 regulatory T cells (Tregs).
Investigators found that, in young, healthy individuals, CD8 Tregs suppress the activation and expansion of CD4 T cells.
However, older individuals and patients with a rare form of vasculitis exhibit CD8 Treg dysfunction, which is tied to a drop in production of an enzyme called NADPH oxidase 2 (NOX2).
Cornelia Weyand, MD, of Stanford University Medical Center in California, and her colleagues conducted this research.
First, the team found that CD8 Tregs preferentially take up residence in lymph nodes, the spleen, and other regions where there are huge “armies” of CD4 T cells. This proximity puts the CD8 Tregs in a position to stamp out CD4 T-cell activation early on.
Further experiments demonstrated that CD8 Tregs manufacture copious amounts of NOX2, which they package into tiny membrane-bound packets and transfer to the surfaces of abutting CD4 T cells.
These NOX2-laden packets are then taken up by the CD4 T cells. Inside their new home, the enzymes produce large volumes of highly reactive signaling substances that dial down CD4 T cells’ activation and proliferation.
The investigators noted that contact between CD8 Tregs and CD4 T cells in the early stages of activation shuts down the CD4 T cells’ activity and reduces their proliferation by half or more, even several days after the CD8 Tregs have been removed. Transferring NOX2 alone onto activated CD4 T cells also produces this effect.
Next, the team analyzed blood samples from healthy individuals and observed that CD8 Tregs were only about half as common in blood from people age 60 and older as in blood from 20- to 30-year-olds.
Both CD8 Treg numbers and their ability to suppress CD4 T-cell proliferation declined with advancing age. Experiments traced this to a drop in NOX2 production by older donors’ CD8 Tregs.
The investigators also discovered CD8 Treg failure in giant-cell arteritis (GCA). The team compared blood from GCA patients to blood from age-matched healthy control subjects and from patients with 2 other autoimmune diseases—psoriatic arthritis and small-vessel vasculitis. This revealed a severe deficit among GCA patients in NOX2-producing CD8 Tregs.
“This tells us that the deficit in NOX2-producing CD8 Tregs is specific to GCA, not just driving or driven by inflammation,” Dr Weyand said. “That’s good news for our patients who have this disease, which has been an enigma. Now we know something about what’s causing it.”
The discovery of NOX2 on the surface of CD8 Tregs—but not on other T-cell types—makes them much easier to identify and count, Dr Weyand added.
She and her colleagues are taking advantage of the new-found biomarker to tally CD8 Tregs in patients with age-associated disorders now understood to be driven by chronic inflammation to see if CD8 Treg deficits underlie some of these conditions’ pathology and whether they may be amenable to potential NOX2-restoring treatments.
Image by Kathryn T. Iacono
Research published in The Journal of Clinical Investigation provides new insights regarding CD8 regulatory T cells (Tregs).
Investigators found that, in young, healthy individuals, CD8 Tregs suppress the activation and expansion of CD4 T cells.
However, older individuals and patients with a rare form of vasculitis exhibit CD8 Treg dysfunction, which is tied to a drop in production of an enzyme called NADPH oxidase 2 (NOX2).
Cornelia Weyand, MD, of Stanford University Medical Center in California, and her colleagues conducted this research.
First, the team found that CD8 Tregs preferentially take up residence in lymph nodes, the spleen, and other regions where there are huge “armies” of CD4 T cells. This proximity puts the CD8 Tregs in a position to stamp out CD4 T-cell activation early on.
Further experiments demonstrated that CD8 Tregs manufacture copious amounts of NOX2, which they package into tiny membrane-bound packets and transfer to the surfaces of abutting CD4 T cells.
These NOX2-laden packets are then taken up by the CD4 T cells. Inside their new home, the enzymes produce large volumes of highly reactive signaling substances that dial down CD4 T cells’ activation and proliferation.
The investigators noted that contact between CD8 Tregs and CD4 T cells in the early stages of activation shuts down the CD4 T cells’ activity and reduces their proliferation by half or more, even several days after the CD8 Tregs have been removed. Transferring NOX2 alone onto activated CD4 T cells also produces this effect.
Next, the team analyzed blood samples from healthy individuals and observed that CD8 Tregs were only about half as common in blood from people age 60 and older as in blood from 20- to 30-year-olds.
Both CD8 Treg numbers and their ability to suppress CD4 T-cell proliferation declined with advancing age. Experiments traced this to a drop in NOX2 production by older donors’ CD8 Tregs.
The investigators also discovered CD8 Treg failure in giant-cell arteritis (GCA). The team compared blood from GCA patients to blood from age-matched healthy control subjects and from patients with 2 other autoimmune diseases—psoriatic arthritis and small-vessel vasculitis. This revealed a severe deficit among GCA patients in NOX2-producing CD8 Tregs.
“This tells us that the deficit in NOX2-producing CD8 Tregs is specific to GCA, not just driving or driven by inflammation,” Dr Weyand said. “That’s good news for our patients who have this disease, which has been an enigma. Now we know something about what’s causing it.”
The discovery of NOX2 on the surface of CD8 Tregs—but not on other T-cell types—makes them much easier to identify and count, Dr Weyand added.
She and her colleagues are taking advantage of the new-found biomarker to tally CD8 Tregs in patients with age-associated disorders now understood to be driven by chronic inflammation to see if CD8 Treg deficits underlie some of these conditions’ pathology and whether they may be amenable to potential NOX2-restoring treatments.