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All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells.

Van YH, Lee WH, Ortiz S, Lee MH, Qin HJ, Liu CP - Diabetes (2008)

Bottom Line: Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression.These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells.Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Beckman Research Institute, City of Hope, Duarte, California, USA.

ABSTRACT

Objective: All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear.

Research design and methods: We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease.

Results: Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-gamma-producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17--or IL-4-producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell-dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion.

Conclusions: These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells.

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ATRA treatment decreases the percentage and number of islet-infiltrating CD8+ T-cells in recipient mice. A: FACS staining of islet-infiltrating cells (left); number of islet-infiltrating CD4+ or CD8+ T-cells isolated from recipient mice (right) at 4 weeks after cell transfer. B: Number of CD4+ and CD8+ T-cells in spleens (SPL), inguinal lymph nodes (ILN), and pancreatic lymph nodes (PLN). NOD/scid mice adoptively transferred with splenocytes isolated from newly diabetic NOD mice treated with vehicle or ATRA as of the day of cell transfer; cells were isolated from recipient mice 4 weeks after cell transfer. Control mice developed diabetes, and ATRA-treated recipient mice remained diabetes free. Numbers of islet-infiltrating CD8+ cells from ATRA-treated mice were significantly lower compared with controls. No difference was noted between control and ATRA-treated mice in islet-infiltrating CD4+ cells and CD4+ and CD8+ T-cells in other tissues (n = 3 experiments). (Please see http://dx.doi.org/10.2337/db08-1154 for a high-quality digital representation of this figure.)
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f2: ATRA treatment decreases the percentage and number of islet-infiltrating CD8+ T-cells in recipient mice. A: FACS staining of islet-infiltrating cells (left); number of islet-infiltrating CD4+ or CD8+ T-cells isolated from recipient mice (right) at 4 weeks after cell transfer. B: Number of CD4+ and CD8+ T-cells in spleens (SPL), inguinal lymph nodes (ILN), and pancreatic lymph nodes (PLN). NOD/scid mice adoptively transferred with splenocytes isolated from newly diabetic NOD mice treated with vehicle or ATRA as of the day of cell transfer; cells were isolated from recipient mice 4 weeks after cell transfer. Control mice developed diabetes, and ATRA-treated recipient mice remained diabetes free. Numbers of islet-infiltrating CD8+ cells from ATRA-treated mice were significantly lower compared with controls. No difference was noted between control and ATRA-treated mice in islet-infiltrating CD4+ cells and CD4+ and CD8+ T-cells in other tissues (n = 3 experiments). (Please see http://dx.doi.org/10.2337/db08-1154 for a high-quality digital representation of this figure.)

Mentions: Several possibilities exist that may explain the inhibition of diabetes development by ATRA, including 1) reduction of Teff cell number, 2) suppression of activation and/or function of Teff cells, and 3) expansion of Treg cell number and/or enhancement of their function. To address these possibilities, we first determined whether ATRA treatment affected the number of CD4+ and CD8+ T-cells present in recipient mice transferred with splenocytes isolated from newly diabetic NOD mice. Our results showed that compared with controls, the percentage and number of islet-infiltrating CD8+ T-cells, but not CD4+ T-cells, was significantly reduced in ATRA-treated nondiabetic mice 4 weeks after cell transfer (Fig. 2A). At this time, all control mice had developed diabetes. ATRA treatment did not affect the number of CD4+ or CD8+ T-cells present in spleen and lymph nodes (Fig. 2B).


All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-gamma-producing T-cells without affecting Th17 cells.

Van YH, Lee WH, Ortiz S, Lee MH, Qin HJ, Liu CP - Diabetes (2008)

ATRA treatment decreases the percentage and number of islet-infiltrating CD8+ T-cells in recipient mice. A: FACS staining of islet-infiltrating cells (left); number of islet-infiltrating CD4+ or CD8+ T-cells isolated from recipient mice (right) at 4 weeks after cell transfer. B: Number of CD4+ and CD8+ T-cells in spleens (SPL), inguinal lymph nodes (ILN), and pancreatic lymph nodes (PLN). NOD/scid mice adoptively transferred with splenocytes isolated from newly diabetic NOD mice treated with vehicle or ATRA as of the day of cell transfer; cells were isolated from recipient mice 4 weeks after cell transfer. Control mice developed diabetes, and ATRA-treated recipient mice remained diabetes free. Numbers of islet-infiltrating CD8+ cells from ATRA-treated mice were significantly lower compared with controls. No difference was noted between control and ATRA-treated mice in islet-infiltrating CD4+ cells and CD4+ and CD8+ T-cells in other tissues (n = 3 experiments). (Please see http://dx.doi.org/10.2337/db08-1154 for a high-quality digital representation of this figure.)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2606864&req=5

f2: ATRA treatment decreases the percentage and number of islet-infiltrating CD8+ T-cells in recipient mice. A: FACS staining of islet-infiltrating cells (left); number of islet-infiltrating CD4+ or CD8+ T-cells isolated from recipient mice (right) at 4 weeks after cell transfer. B: Number of CD4+ and CD8+ T-cells in spleens (SPL), inguinal lymph nodes (ILN), and pancreatic lymph nodes (PLN). NOD/scid mice adoptively transferred with splenocytes isolated from newly diabetic NOD mice treated with vehicle or ATRA as of the day of cell transfer; cells were isolated from recipient mice 4 weeks after cell transfer. Control mice developed diabetes, and ATRA-treated recipient mice remained diabetes free. Numbers of islet-infiltrating CD8+ cells from ATRA-treated mice were significantly lower compared with controls. No difference was noted between control and ATRA-treated mice in islet-infiltrating CD4+ cells and CD4+ and CD8+ T-cells in other tissues (n = 3 experiments). (Please see http://dx.doi.org/10.2337/db08-1154 for a high-quality digital representation of this figure.)
Mentions: Several possibilities exist that may explain the inhibition of diabetes development by ATRA, including 1) reduction of Teff cell number, 2) suppression of activation and/or function of Teff cells, and 3) expansion of Treg cell number and/or enhancement of their function. To address these possibilities, we first determined whether ATRA treatment affected the number of CD4+ and CD8+ T-cells present in recipient mice transferred with splenocytes isolated from newly diabetic NOD mice. Our results showed that compared with controls, the percentage and number of islet-infiltrating CD8+ T-cells, but not CD4+ T-cells, was significantly reduced in ATRA-treated nondiabetic mice 4 weeks after cell transfer (Fig. 2A). At this time, all control mice had developed diabetes. ATRA treatment did not affect the number of CD4+ or CD8+ T-cells present in spleen and lymph nodes (Fig. 2B).

Bottom Line: Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression.These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells.Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells.

View Article: PubMed Central - PubMed

Affiliation: Division of Immunology, Beckman Research Institute, City of Hope, Duarte, California, USA.

ABSTRACT

Objective: All-trans retinoic acid (ATRA), a potent derivative of vitamin A, can regulate immune responses. However, its role in inducing immune tolerance associated with the prevention of islet inflammation and inhibition of type 1 diabetes remains unclear.

Research design and methods: We investigated the mechanisms underlying the potential immunoregulatory effect of ATRA on type 1 diabetes using an adoptive transfer animal model of the disease.

Results: Our data demonstrated that ATRA treatment inhibited diabetes in NOD mice with established insulitis. In addition, it suppressed interferon (IFN)-gamma-producing CD4(+) and CD8(+) T effector (Teff) cells and expanded T regulatory (Treg) cells in recipient mice transferred with diabetic NOD splenocytes, without affecting either interleukin (IL)-17--or IL-4-producing cells. Consistent with these results, ATRA reduced T-bet and STAT4 expression in T-cells and decreased islet-infiltrating CD8(+) T-cells, suppressing their activation and IFN-gamma/granzyme B expression. Depletion of CD4(+)CD25(+) Treg cells impaired the inhibitory effect of ATRA on islet-infiltrating T-cells and blocked its protective effect on diabetes. Therefore, ATRA treatment induced Treg cell-dependent immune tolerance by suppressing both CD4(+) and CD8(+) Teff cells while promoting Treg cell expansion.

Conclusions: These results demonstrate that ATRA treatment promoted in vivo expansion of Treg cells and induced Treg cell-dependent immune tolerance by suppressing IFN-gamma-producing T-cells, without affecting Th17 cells. Our study also provides novel insights into how ATRA induces immune tolerance in vivo via its effects on Teff and Treg cells.

Show MeSH
Related in: MedlinePlus