Ana Izcue - Academia.edu (original) (raw)

Papers by Ana Izcue

Immunology, 2017

CD4(+) Foxp3(+) regulatory T cells (Treg) include differentiated populations of effector Treg cha... more CD4(+) Foxp3(+) regulatory T cells (Treg) include differentiated populations of effector Treg characterized by the expression of specific transcription factors. Tumors, including intestinal malignancies, often present with local accumulation of Treg that can prevent tumor clearance, but how tumor progression leads to Treg accumulation is incompletely understood. Here using genetically modified mouse models we show that ablation of E-cadherin, a process associated with epithelial to mesenchymal transition (EMT) and tumor progression, promotes the accumulation of intestinal Treg by the specific accumulation of the KLRG1(+) GATA3(+) Treg subset. Epithelial E-cadherin ablation activates the β-catenin pathway, and we find that increasing β-catenin signals in intestinal epithelial cells also boosts Treg frequencies through local accumulation of KLRG1(+) GATA3(+) Treg. Both E-cadherin ablation and increased β-catenin signals resulted in epithelial cells with higher levels of IL-33, a cytokine that preferentially expands KLRG1(+) GATA3(+) Treg. Tumors often present reduced E-cadherin expression and increased β-catenin signaling and IL-33 production. Accordingly, Treg accumulation in intestinal tumors from APC(min/+) mice was exclusively due to the increase in KLRG1(+) GATA3(+) Treg. Our data identify a novel axis through which epithelial cells control local Treg cell subsets, which may be activated during intestinal tumorigenesis. This article is protected by copyright. All rights reserved.

Immunology, 2017

Immune homeostasis requires the tight, tissue-specific control of the different CD4(+) Foxp3(+) r... more Immune homeostasis requires the tight, tissue-specific control of the different CD4(+) Foxp3(+) regulatory T cells (Treg) populations. The cadherin-binding inhibitory receptor KLRG1 is expressed by a subpopulation of Treg with GATA3(+) effector phenotype. Although such Treg are important for the immune balance, especially in the gut, the role of KLRG1 in Treg has not been assessed. Using KLRG1 KO mice, we found that KLRG1 deficiency does not affect Treg frequencies in spleen, mesenteric lymph nodes or intestine, or frequencies of GATA3(+) Treg in the gut. KLRG1-deficient Treg were also protective in a T cell transfer model of colitis. Hence, KLRG1 is not essential for the development or activity of the general Treg population. We then checked the effects of KLRG1 on Treg activation. In line with KLRG1's reported inhibitory activity, in vitro KLRG1 crosslinking dampened Treg TCR response. Consistently, lack of KLRG1 on Treg conferred them a competitive advantage in the gut, but not in lymphoid organs. Hence, although absence of KLRG1 is not enough to increase intestinal Treg in KLRG1 KO mice, KLRG1 ligation reduces TCR signals and the competitive fitness of individual Treg in the intestine. This article is protected by copyright. All rights reserved.

Investigacion Y Ciencia, 2013

PLOS ONE, 2015

T lymphocytes elicit specific responses after recognizing cognate antigen. However, antigen-exper... more T lymphocytes elicit specific responses after recognizing cognate antigen. However, antigen-experienced T cells can also respond to non-cognate stimuli, such as cytokines. CD4+ Foxp3+ regulatory T cells (Treg) exhibit an antigen-experienced-like phenotype. Treg can regulate T cell responses in an antigen-specific or bystander way, and it is still unclear as to which extent they rely on T cell receptor (TCR) signals. The study of the antigen response of Treg has been hampered by the lack of downstream readouts for TCR stimuli. Here we assess the effects of TCR signals on the expression of a classical marker of early T cell activation, CD69. Although it can be induced following cytokine exposure, CD69 is commonly used as a readout for antigen response on T cells. We established that upon in vitro TCR stimulation CD69 induction on Foxp3+ Treg cells was more dependent on signaling via soluble factors than on TCR activation. By contrast, expression of the activation marker Nur77 was only induced after TCR stimulation. Our data suggest that Treg are more sensitive to TCR-independent signals than Foxp3- cells, which could contribute to their bystander activity.

European journal of immunology, 2005

Regulatory T cells (TR cells) play a major role in controlling immune self reactivity. However, l... more Regulatory T cells (TR cells) play a major role in controlling immune self reactivity. However, little is known about their occurrence and functions in early developmental stages. In this issue of the European Journal of Immunology, Cupedo et al. report the presence of functional CD4+CD25+ TR cells in the human fetus. In contrast to previous studies, the analysis is performed on fetal thymus, spleen and lymph node samples in addition to cord blood cells. Interestingly, TR cells are present in all these organs from 14 weeks of gestation, along with FoxP3 (forkhead box protein 3) RNA, a marker for naturally arising TR cells. The fetal TR cells show, however, phenotypic differences depending on their location, possibly because of variations in their activation state. The emergence of TR cells so early in fetal development raises a number of questions about the mechanisms of self reactivity and tolerance in the prenatal stages, which may have important implications for our understanding...

Immunology, 2008

Tolerance to self and harmless antigens is one of the central features of the immune system, and ... more Tolerance to self and harmless antigens is one of the central features of the immune system, and it is obtained through a combination of multiple mechanisms. Discriminating between pathogens and non-pathogenic antigens is especially important in the intestine, which constitutes the main contact surface between the body and the outside environment. Recently, the role of Foxp3 + regulatory T cells (Treg) in the establishment and maintenance of tolerance has been the focus of numerous studies. In this review, we briefly discuss the historical background leading to the identification of Foxp3 + Treg and give an overview of their role in controlling systemic and mucosal immune responses.

Immunological Reviews, 2008

Immunological Reviews, 2006

The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigen... more The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way.

European Journal of Immunology, 2005

Annual Review of Immunology, 2009

The immune system is pivotal in mediating the interactions between host and microbiota that shape... more The immune system is pivotal in mediating the interactions between host and microbiota that shape the intestinal environment. Intestinal homeostasis arises from a highly dynamic balance between host protective immunity and regulatory mechanisms. This regulation is achieved by a number of cell populations acting through a set of shared regulatory pathways. In this review, we summarize the main lymphocyte subsets controlling immune responsiveness in the gut and their mechanisms of control, which involve maintenance of intestinal barrier function and suppression of chronic inflammation. CD4(+)Foxp3(+) T cells play a nonredundant role in the maintenance of intestinal homeostasis through IL-10- and TGF-beta-dependent mechanisms. Their activity is complemented by other T and B lymphocytes. Because breakdown in immune regulatory networks in the intestine leads to chronic inflammatory diseases of the gut, such as inflammatory bowel disease and celiac disease, regulatory lymphocytes are an attractive target for therapies of intestinal inflammation.

Proceedings of the National Academy of Sciences, 2011

CD1d-restricted invariant NKT (iNKT) cells are a unique lineage of T lymphocytes that regulate bo... more CD1d-restricted invariant NKT (iNKT) cells are a unique lineage of T lymphocytes that regulate both innate and adaptive immunity. The Mediator complex forms the bridge between transcriptional activators and the general transcription machinery. Med1/ TRAP220 (also called DRIP205) is a key component of Mediator that interacts with ligand-bound hormone receptors, such as the vitamin D receptor. Here, we show that T-cell-specific Med1 deficiency results in a specific block in iNKT cell development but the development of conventional αβ T cells remains grossly normal. The defect is cell-intrinsic and depends neither on apoptosis, cellcycle control, nor on CD1d expression of CD4 + CD8 + double-positive thymocytes. Surprisingly, ectopic expression of a Vα14-Jα18 T-cell receptor transgene completely rescues the defect caused by Med1 deficiency. At the molecular level, thymic iNKT cells in Med1 −/− animals display reduced levels of IL-2Rβ and T-bet expression and could not complete terminal maturation. Thus, Med1 is essential for a complete intrathymic development of iNKT cells.

The Journal of Immunology, 2006

CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell... more CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell transfer model of colitis. Using Foxp3 as a marker of regulatory T cell activity, we now provide a comprehensive analysis of the in vivo distribution of Foxp3+CD4+CD25+ cells in wild-type mice, and during cure of experimental colitis. In both cases, Foxp3+CD4+CD25+ cells were found to accumulate in the colon and secondary lymphoid organs. Importantly, Foxp3+ cells were present at increased density in colon samples from patients with ulcerative colitis or Crohn's disease, suggesting similarities in the behavior of murine and human regulatory cells under inflammatory conditions. Cure of murine colitis was dependent on the presence of IL-10, and IL-10-producing CD4+CD25+ T cells were enriched within the colon during cure of colitis and also under steady state conditions. Our data indicate that although CD4+CD25+ T cells expressing Foxp3 are present within both lymphoid organs and the colon, subsets of IL-10-producing CD4+CD25+ T cells are present mainly within the intestinal lamina propria suggesting compartmentalization of the regulatory T cell response at effector sites.

The Journal of Immunology, 2006

Naturally occurring CD4 ؉ regulatory T cells (T R ) that express CD25 and the transcription facto... more Naturally occurring CD4 ؉ regulatory T cells (T R ) that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis, preventing immune pathological responses to self and foreign Ags. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for T R in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in T R function. In this study, using a T cell-mediated colitis model, we demonstrate that anti-CTLA-4 mAb treatment inhibits T R function in vivo via direct effects on CTLA-4-expressing T R , and not via hyperactivation of colitogenic effector T cells. Although anti-CTLA-4 mAb treatment completely inhibits T R function, it does not reduce T R numbers or their homing to the GALT, suggesting the Ab mediates its function by blockade of a signal required for T R activity. In contrast to the striking effect of the Ab, CTLA-4-deficient mice can produce functional T R , suggesting that under some circumstances other immune regulatory mechanisms, including the production of IL-10, are able to compensate for the loss of the CTLA-4-mediated pathway. This study provides direct evidence that CTLA-4 has a specific, nonredundant role in the function of normal T R . This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break T R -mediated self-tolerance.

Immunity, 2008

Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of s... more Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3 + cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.

European Journal of Immunology, 2001

Endogenous superantigens (SAg) presented by MHC class II IA molecules induce slowevolving negativ... more Endogenous superantigens (SAg) presented by MHC class II IA molecules induce slowevolving negative selection of § g T cells. The role of both B and +ˇT cells on the regulation of these SAg-specific § g T cell responses was addressed in IA b+ IE b-C57BL/6 mice bearing genetically induced B cell and +ˇT cell deficiencies. B lymphocytes were required in the negative selection of V g 5 + /V g 12 + CD4 + T cells. In contrast, +ˇT cells positively stimulated the utilization of the same SAg-responsive § g T cell subsets. These differences started in mature CD4 + thymocytes and extended to naive T cell pools for B cell negative selection, and up to memory T cells for +ˇT cell influences. The levels of SAg-responsive T cells did not vary between C57BL/6 and double deficient (B cell and +ˇT cell-deficient) congenic mice, implying that both B and +ˇT cells acted through independent mechanisms.

Immunology, 2017

CD4(+) Foxp3(+) regulatory T cells (Treg) include differentiated populations of effector Treg cha... more CD4(+) Foxp3(+) regulatory T cells (Treg) include differentiated populations of effector Treg characterized by the expression of specific transcription factors. Tumors, including intestinal malignancies, often present with local accumulation of Treg that can prevent tumor clearance, but how tumor progression leads to Treg accumulation is incompletely understood. Here using genetically modified mouse models we show that ablation of E-cadherin, a process associated with epithelial to mesenchymal transition (EMT) and tumor progression, promotes the accumulation of intestinal Treg by the specific accumulation of the KLRG1(+) GATA3(+) Treg subset. Epithelial E-cadherin ablation activates the β-catenin pathway, and we find that increasing β-catenin signals in intestinal epithelial cells also boosts Treg frequencies through local accumulation of KLRG1(+) GATA3(+) Treg. Both E-cadherin ablation and increased β-catenin signals resulted in epithelial cells with higher levels of IL-33, a cytokine that preferentially expands KLRG1(+) GATA3(+) Treg. Tumors often present reduced E-cadherin expression and increased β-catenin signaling and IL-33 production. Accordingly, Treg accumulation in intestinal tumors from APC(min/+) mice was exclusively due to the increase in KLRG1(+) GATA3(+) Treg. Our data identify a novel axis through which epithelial cells control local Treg cell subsets, which may be activated during intestinal tumorigenesis. This article is protected by copyright. All rights reserved.

Immunology, 2017

Immune homeostasis requires the tight, tissue-specific control of the different CD4(+) Foxp3(+) r... more Immune homeostasis requires the tight, tissue-specific control of the different CD4(+) Foxp3(+) regulatory T cells (Treg) populations. The cadherin-binding inhibitory receptor KLRG1 is expressed by a subpopulation of Treg with GATA3(+) effector phenotype. Although such Treg are important for the immune balance, especially in the gut, the role of KLRG1 in Treg has not been assessed. Using KLRG1 KO mice, we found that KLRG1 deficiency does not affect Treg frequencies in spleen, mesenteric lymph nodes or intestine, or frequencies of GATA3(+) Treg in the gut. KLRG1-deficient Treg were also protective in a T cell transfer model of colitis. Hence, KLRG1 is not essential for the development or activity of the general Treg population. We then checked the effects of KLRG1 on Treg activation. In line with KLRG1's reported inhibitory activity, in vitro KLRG1 crosslinking dampened Treg TCR response. Consistently, lack of KLRG1 on Treg conferred them a competitive advantage in the gut, but not in lymphoid organs. Hence, although absence of KLRG1 is not enough to increase intestinal Treg in KLRG1 KO mice, KLRG1 ligation reduces TCR signals and the competitive fitness of individual Treg in the intestine. This article is protected by copyright. All rights reserved.

Investigacion Y Ciencia, 2013

PLOS ONE, 2015

T lymphocytes elicit specific responses after recognizing cognate antigen. However, antigen-exper... more T lymphocytes elicit specific responses after recognizing cognate antigen. However, antigen-experienced T cells can also respond to non-cognate stimuli, such as cytokines. CD4+ Foxp3+ regulatory T cells (Treg) exhibit an antigen-experienced-like phenotype. Treg can regulate T cell responses in an antigen-specific or bystander way, and it is still unclear as to which extent they rely on T cell receptor (TCR) signals. The study of the antigen response of Treg has been hampered by the lack of downstream readouts for TCR stimuli. Here we assess the effects of TCR signals on the expression of a classical marker of early T cell activation, CD69. Although it can be induced following cytokine exposure, CD69 is commonly used as a readout for antigen response on T cells. We established that upon in vitro TCR stimulation CD69 induction on Foxp3+ Treg cells was more dependent on signaling via soluble factors than on TCR activation. By contrast, expression of the activation marker Nur77 was only induced after TCR stimulation. Our data suggest that Treg are more sensitive to TCR-independent signals than Foxp3- cells, which could contribute to their bystander activity.

European journal of immunology, 2005

Regulatory T cells (TR cells) play a major role in controlling immune self reactivity. However, l... more Regulatory T cells (TR cells) play a major role in controlling immune self reactivity. However, little is known about their occurrence and functions in early developmental stages. In this issue of the European Journal of Immunology, Cupedo et al. report the presence of functional CD4+CD25+ TR cells in the human fetus. In contrast to previous studies, the analysis is performed on fetal thymus, spleen and lymph node samples in addition to cord blood cells. Interestingly, TR cells are present in all these organs from 14 weeks of gestation, along with FoxP3 (forkhead box protein 3) RNA, a marker for naturally arising TR cells. The fetal TR cells show, however, phenotypic differences depending on their location, possibly because of variations in their activation state. The emergence of TR cells so early in fetal development raises a number of questions about the mechanisms of self reactivity and tolerance in the prenatal stages, which may have important implications for our understanding...

Immunology, 2008

Tolerance to self and harmless antigens is one of the central features of the immune system, and ... more Tolerance to self and harmless antigens is one of the central features of the immune system, and it is obtained through a combination of multiple mechanisms. Discriminating between pathogens and non-pathogenic antigens is especially important in the intestine, which constitutes the main contact surface between the body and the outside environment. Recently, the role of Foxp3 + regulatory T cells (Treg) in the establishment and maintenance of tolerance has been the focus of numerous studies. In this review, we briefly discuss the historical background leading to the identification of Foxp3 + Treg and give an overview of their role in controlling systemic and mucosal immune responses.

Immunological Reviews, 2008

Immunological Reviews, 2006

The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigen... more The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way.

European Journal of Immunology, 2005

Annual Review of Immunology, 2009

The immune system is pivotal in mediating the interactions between host and microbiota that shape... more The immune system is pivotal in mediating the interactions between host and microbiota that shape the intestinal environment. Intestinal homeostasis arises from a highly dynamic balance between host protective immunity and regulatory mechanisms. This regulation is achieved by a number of cell populations acting through a set of shared regulatory pathways. In this review, we summarize the main lymphocyte subsets controlling immune responsiveness in the gut and their mechanisms of control, which involve maintenance of intestinal barrier function and suppression of chronic inflammation. CD4(+)Foxp3(+) T cells play a nonredundant role in the maintenance of intestinal homeostasis through IL-10- and TGF-beta-dependent mechanisms. Their activity is complemented by other T and B lymphocytes. Because breakdown in immune regulatory networks in the intestine leads to chronic inflammatory diseases of the gut, such as inflammatory bowel disease and celiac disease, regulatory lymphocytes are an attractive target for therapies of intestinal inflammation.

Proceedings of the National Academy of Sciences, 2011

CD1d-restricted invariant NKT (iNKT) cells are a unique lineage of T lymphocytes that regulate bo... more CD1d-restricted invariant NKT (iNKT) cells are a unique lineage of T lymphocytes that regulate both innate and adaptive immunity. The Mediator complex forms the bridge between transcriptional activators and the general transcription machinery. Med1/ TRAP220 (also called DRIP205) is a key component of Mediator that interacts with ligand-bound hormone receptors, such as the vitamin D receptor. Here, we show that T-cell-specific Med1 deficiency results in a specific block in iNKT cell development but the development of conventional αβ T cells remains grossly normal. The defect is cell-intrinsic and depends neither on apoptosis, cellcycle control, nor on CD1d expression of CD4 + CD8 + double-positive thymocytes. Surprisingly, ectopic expression of a Vα14-Jα18 T-cell receptor transgene completely rescues the defect caused by Med1 deficiency. At the molecular level, thymic iNKT cells in Med1 −/− animals display reduced levels of IL-2Rβ and T-bet expression and could not complete terminal maturation. Thus, Med1 is essential for a complete intrathymic development of iNKT cells.

The Journal of Immunology, 2006

CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell... more CD4+CD25+ regulatory T cells can prevent and resolve intestinal inflammation in the murine T cell transfer model of colitis. Using Foxp3 as a marker of regulatory T cell activity, we now provide a comprehensive analysis of the in vivo distribution of Foxp3+CD4+CD25+ cells in wild-type mice, and during cure of experimental colitis. In both cases, Foxp3+CD4+CD25+ cells were found to accumulate in the colon and secondary lymphoid organs. Importantly, Foxp3+ cells were present at increased density in colon samples from patients with ulcerative colitis or Crohn's disease, suggesting similarities in the behavior of murine and human regulatory cells under inflammatory conditions. Cure of murine colitis was dependent on the presence of IL-10, and IL-10-producing CD4+CD25+ T cells were enriched within the colon during cure of colitis and also under steady state conditions. Our data indicate that although CD4+CD25+ T cells expressing Foxp3 are present within both lymphoid organs and the colon, subsets of IL-10-producing CD4+CD25+ T cells are present mainly within the intestinal lamina propria suggesting compartmentalization of the regulatory T cell response at effector sites.

The Journal of Immunology, 2006

Naturally occurring CD4 ؉ regulatory T cells (T R ) that express CD25 and the transcription facto... more Naturally occurring CD4 ؉ regulatory T cells (T R ) that express CD25 and the transcription factor FoxP3 play a key role in immune homeostasis, preventing immune pathological responses to self and foreign Ags. CTLA-4 is expressed by a high percentage of these cells, and is often considered as a marker for T R in experimental and clinical analysis. However, it has not yet been proven that CTLA-4 has a direct role in T R function. In this study, using a T cell-mediated colitis model, we demonstrate that anti-CTLA-4 mAb treatment inhibits T R function in vivo via direct effects on CTLA-4-expressing T R , and not via hyperactivation of colitogenic effector T cells. Although anti-CTLA-4 mAb treatment completely inhibits T R function, it does not reduce T R numbers or their homing to the GALT, suggesting the Ab mediates its function by blockade of a signal required for T R activity. In contrast to the striking effect of the Ab, CTLA-4-deficient mice can produce functional T R , suggesting that under some circumstances other immune regulatory mechanisms, including the production of IL-10, are able to compensate for the loss of the CTLA-4-mediated pathway. This study provides direct evidence that CTLA-4 has a specific, nonredundant role in the function of normal T R . This role has to be taken into account when targeting CTLA-4 for therapeutic purposes, as such a strategy will not only boost effector T cell responses, but might also break T R -mediated self-tolerance.

Immunity, 2008

Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of s... more Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3 + cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.

European Journal of Immunology, 2001

Endogenous superantigens (SAg) presented by MHC class II IA molecules induce slowevolving negativ... more Endogenous superantigens (SAg) presented by MHC class II IA molecules induce slowevolving negative selection of § g T cells. The role of both B and +ˇT cells on the regulation of these SAg-specific § g T cell responses was addressed in IA b+ IE b-C57BL/6 mice bearing genetically induced B cell and +ˇT cell deficiencies. B lymphocytes were required in the negative selection of V g 5 + /V g 12 + CD4 + T cells. In contrast, +ˇT cells positively stimulated the utilization of the same SAg-responsive § g T cell subsets. These differences started in mature CD4 + thymocytes and extended to naive T cell pools for B cell negative selection, and up to memory T cells for +ˇT cell influences. The levels of SAg-responsive T cells did not vary between C57BL/6 and double deficient (B cell and +ˇT cell-deficient) congenic mice, implying that both B and +ˇT cells acted through independent mechanisms.