Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease

Paust, Silke; Lu, Linrong; McCarty, Nami; Cantor, Harvey

doi:10.1073/pnas.0403342101

Cited by 285 publications

(209 citation statements)

References 35 publications

(27 reference statements)

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“…However, our observation in this regard is preliminary in scope and limited to the target tissue, and thus does not invalidate the hypothesis that CTLA4 expressed by T reg cells may bind to CD80/CD86 on T eff cells to facilitate direct cellular interactions (Paust et al, 2004). On the other hand, the data from our studies suggest that CTLA4 might affect T reg -T eff cell interaction through other mechanisms.…”

Section: Methodscontrasting

confidence: 47%

“…A previous study (Paust et al, 2004) reported that CD80/CD86-deficient T eff cells were resistant to T reg cell suppression. We explored along this line but did not detect expression of CD80 or CD86 on T reg cells or T eff cells in the target tissues by cytolableing in situ with specific antibodies, T eff cells (n = 3 mice, 40 cells, mean ± SEM) in ACE islet grafts in B6 mice is compared with that of CD4 + BDC2.5 T cells in ACE islet grafts in NOD.…”

Section: Ar Ticlementioning

confidence: 99%

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Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

Jason¹,

Abdulreda²,

Devarajan³

et al. 2014

J Cell Biol

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Real-time imaging studies are reshaping immunological paradigms, but a visual framework is lacking for self-antigen-specific T cells at the effector phase in target tissues. To address this issue, we conducted intravital, longitudinal imaging analyses of cellular behavior in nonlymphoid target tissues to illustrate some key aspects of T cell biology. We used mouse models of T cell-mediated damage and protection of pancreatic islet grafts. Both CD4 + and CD8 + effector T (T eff ) lymphocytes directly engaged target cells. Strikingly, juxtaposed  cells lacking specific antigens were not subject to bystander destruction but grew substantially in days, likely by replication. In target tissue, Foxp3 + regulatory T (T reg ) cells persistently contacted T eff cells with or without involvement of CD11c + dendritic cells, an observation conciliating with the in vitro "trademark" of T reg function, contact-dependent suppression. This study illustrates tolerance induction by contact-based immune cell interaction in target tissues and highlights potentials of tissue regeneration under antigenic incognito in inflammatory settings.

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Section: Methodscontrasting

confidence: 47%

Section: Ar Ticlementioning

confidence: 99%

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

Jason¹,

Abdulreda²,

Devarajan³

et al. 2014

J Cell Biol

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“…S4B). Importantly, B7.1 and B7.2 surface expression was clearly detectable on both CD25 -CD4 + responder T cells as well as in CD25 + CD4 + T R cells (data not shown) [26,39]. Next, we asked whether B7 expression on activated T cells is necessary to effect T Rsuppressive activity using cells from B7-deficient mice (B7DKO).…”

Section: Absence Of B7 From Responder T Cells Accounts For Limited Icmentioning

confidence: 99%

“…However, IDO does not seem to be an exclusive mechanism of suppression since direct T R -mediated suppression can be achieved even in the absence of APC at least in vitro [24]. Additional evidence supports the possibility of a similar direct effect on T cells, which up-regulate both B7.1 and B7.2 following TCR activation [25,26]. Therefore, B7 expression on T cells is likely to be relevant since T R cells effectively limit B7 expression on DC [27].…”

Section: Introductionmentioning

confidence: 99%

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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“…The absence of these molecules from effector T cells reduced the cell susceptibility to the suppression by CD4 þ CD25 þ Treg. 12,13 In addition, some members of Tolllike receptor (TLR), which constitutively expressed on Treg, such as TLR 2 and TLR8, might participate in the Treg activation and expansion. [14][15][16] Cytolytic activity was invoked as a possible mechanism of suppression by Treg.…”

mentioning

confidence: 99%

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

et al. 2007

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CD4 þ CD25 þ regulatory T cells (Treg) are potent immunosuppressive cells active in controlling normal pathological immune responses. The mechanisms of this suppression have been investigated under various conditions. In this report, tumor necrosis factor-related apoptosis inducing ligand (TRAIL)/death receptor 5 (DR5) was explored as one of the pivotal factors for the suppression and cytotoxicity induced by CD4 þ CD25 þ Treg. Cell death was involved in the suppression induced by activated CD4 þ CD25 þ Treg in vitro. The induction of CD4 þ T cell death was not mediated by the CD95/CD95L pathway, but rather depended upon the upregulation of TRAIL in the Treg. Blocking the TRAIL/DR5 pathway resulted in a significant reduction of the suppressive activity as well as the cytotoxic effects of Treg in vitro. Activated Treg displayed TRAIL-dependent cytotoxicity against CD4 þ T cells in vivo. The prolonged survival of allogeneic skin grafts induced by Treg was inhibited by DR5-blocking antibodies. Our findings suggest that the TRAIL/DR5 pathway is one of the mechanisms used by Treg to regulate immune responses both in vitro and in vivo.

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Engagement of B7 on effector T cells by regulatory T cells prevents autoimmune disease

Cited by 285 publications

References 35 publications

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

Real-time immune cell interactions in target tissue during autoimmune-induced damage and graft tolerance

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

Involvement of cellular death in TRAIL/DR5-dependent suppression induced by CD4+CD25+ regulatory T cells

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