Limits...
Spontaneous proliferation of H2M-/- CD4 T cells results in unusual acute hepatocellular necrosis.

Do JS, Baldwin WM, Min B - PLoS ONE (2014)

Bottom Line: We found that H2M-/- CD4 T cells undergo robust spontaneous proliferation, differentiate into IFNγ-producing Th1 type effector cells, and, most unexpectedly, induce severe acute hepatocellular necrosis.Interestingly, B cells are fully capable of preventing necrotic inflammation via IL-10-independent and B7-H1-dependent mechanism.This could be a useful animal model to examine T cell-mediated liver inflammation and B cell-mediated immune regulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.

ABSTRACT
Naïve CD4 T cells are triggered to undergo spontaneous proliferation, a proliferative response induced in response to homeostatic stimulation, when exposed to severe lymphopenic environments. They spontaneously acquire proinflammatory effector phenotypes, playing a major role in inducing chronic inflammation in the intestine that is believed to be induced by T cell recognition of commensal antigens. While the antigens inducing the T cell responses and inflammation are being extensively investigated, the role of clonality of T cells involved in this process remains poorly understood. In this study, we utilized naïve CD4 T cells isolated from B6 H2M-/- mice, in which MHCII molecules are complexed with a single CLIP molecule, and examined spontaneous proliferation and intestinal inflammation of CD4 T cells expressing limited T cell receptor repertoire diversity. We found that H2M-/- CD4 T cells undergo robust spontaneous proliferation, differentiate into IFNγ-producing Th1 type effector cells, and, most unexpectedly, induce severe acute hepatocellular necrosis. T cell interaction with MHCII molecule on cells of hematopoietic origin was essential to induce the pathology. Interestingly, B cells are fully capable of preventing necrotic inflammation via IL-10-independent and B7-H1-dependent mechanism. This could be a useful animal model to examine T cell-mediated liver inflammation and B cell-mediated immune regulation.

Show MeSH

Related in: MedlinePlus

IFNγ is a key mediator of liver inflammation.(A) H2M−/− and GKO H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (B) H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− and IFNγR−/− Rag−/− recipients. Liver pathology was determined at 7 days post transfer. Representative pictures from three independent recipients are shown.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4196993&req=5

pone-0110516-g006: IFNγ is a key mediator of liver inflammation.(A) H2M−/− and GKO H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (B) H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− and IFNγR−/− Rag−/− recipients. Liver pathology was determined at 7 days post transfer. Representative pictures from three independent recipients are shown.

Mentions: H2M−/− CD4 T cells mediating unusual necrotic inflammation specifically in the liver primarily produce IFNγ during spontaneous proliferation. To examine whether IFNγ produced by H2M−/− CD4 cells mediate the inflammation, we transferred IFNγ−/− H2M−/− CD4 T cells into Rag−/− mice. As shown in Fig. 6A, the lack of IFNγ production by T cells completely abolished the pathogenicity. Likewise, IFNγR−/− Rag−/− recipients of WT H2M−/− CD4 T cells did not develop inflammation (Fig. 6B). Therefore, these results strongly suggest that IFNγ produced by activated T cells is a direct mediator of the inflammation.


Spontaneous proliferation of H2M-/- CD4 T cells results in unusual acute hepatocellular necrosis.

Do JS, Baldwin WM, Min B - PLoS ONE (2014)

IFNγ is a key mediator of liver inflammation.(A) H2M−/− and GKO H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (B) H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− and IFNγR−/− Rag−/− recipients. Liver pathology was determined at 7 days post transfer. Representative pictures from three independent recipients are shown.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196993&req=5

pone-0110516-g006: IFNγ is a key mediator of liver inflammation.(A) H2M−/− and GKO H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (B) H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− and IFNγR−/− Rag−/− recipients. Liver pathology was determined at 7 days post transfer. Representative pictures from three independent recipients are shown.
Mentions: H2M−/− CD4 T cells mediating unusual necrotic inflammation specifically in the liver primarily produce IFNγ during spontaneous proliferation. To examine whether IFNγ produced by H2M−/− CD4 cells mediate the inflammation, we transferred IFNγ−/− H2M−/− CD4 T cells into Rag−/− mice. As shown in Fig. 6A, the lack of IFNγ production by T cells completely abolished the pathogenicity. Likewise, IFNγR−/− Rag−/− recipients of WT H2M−/− CD4 T cells did not develop inflammation (Fig. 6B). Therefore, these results strongly suggest that IFNγ produced by activated T cells is a direct mediator of the inflammation.

Bottom Line: We found that H2M-/- CD4 T cells undergo robust spontaneous proliferation, differentiate into IFNγ-producing Th1 type effector cells, and, most unexpectedly, induce severe acute hepatocellular necrosis.Interestingly, B cells are fully capable of preventing necrotic inflammation via IL-10-independent and B7-H1-dependent mechanism.This could be a useful animal model to examine T cell-mediated liver inflammation and B cell-mediated immune regulation.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio, United States of America.

ABSTRACT
Naïve CD4 T cells are triggered to undergo spontaneous proliferation, a proliferative response induced in response to homeostatic stimulation, when exposed to severe lymphopenic environments. They spontaneously acquire proinflammatory effector phenotypes, playing a major role in inducing chronic inflammation in the intestine that is believed to be induced by T cell recognition of commensal antigens. While the antigens inducing the T cell responses and inflammation are being extensively investigated, the role of clonality of T cells involved in this process remains poorly understood. In this study, we utilized naïve CD4 T cells isolated from B6 H2M-/- mice, in which MHCII molecules are complexed with a single CLIP molecule, and examined spontaneous proliferation and intestinal inflammation of CD4 T cells expressing limited T cell receptor repertoire diversity. We found that H2M-/- CD4 T cells undergo robust spontaneous proliferation, differentiate into IFNγ-producing Th1 type effector cells, and, most unexpectedly, induce severe acute hepatocellular necrosis. T cell interaction with MHCII molecule on cells of hematopoietic origin was essential to induce the pathology. Interestingly, B cells are fully capable of preventing necrotic inflammation via IL-10-independent and B7-H1-dependent mechanism. This could be a useful animal model to examine T cell-mediated liver inflammation and B cell-mediated immune regulation.

Show MeSH
Related in: MedlinePlus