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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.

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H2M−/− CD4 T cells induce severe necrotic inflammation in the liver.WT and H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (A) Weight loss and (B) survival were monitored after CD4 T cell transfer. Data are the mean ± SD of 4–9 individually tested animals from 2–3 independent experiments. (C) Liver picture and H&E stain of liver, (D) absolute number of donor CD4 T cells in different tissue, and (E) intracellular cytokine expression of the donor cells from the indicated tissues were determined 7 days post transfer. (F) Immunohistochemistry analysis of the CD3+ cells in the liver. Each symbol represents individually tested animals from two independent experiments. *, p<0.05; ***, p<0.001.
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pone-0110516-g001: H2M−/− CD4 T cells induce severe necrotic inflammation in the liver.WT and H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (A) Weight loss and (B) survival were monitored after CD4 T cell transfer. Data are the mean ± SD of 4–9 individually tested animals from 2–3 independent experiments. (C) Liver picture and H&E stain of liver, (D) absolute number of donor CD4 T cells in different tissue, and (E) intracellular cytokine expression of the donor cells from the indicated tissues were determined 7 days post transfer. (F) Immunohistochemistry analysis of the CD3+ cells in the liver. Each symbol represents individually tested animals from two independent experiments. *, p<0.05; ***, p<0.001.

Mentions: When naïve CD4 T cells are transferred into severe lymphopenic hosts they undergo rapid spontaneous proliferation and develop into colitogenic effector cells producing IFNγ and/or IL-17 in response to antigens derived from commensal bacteria and self [2]. By transferring naïve phenotype (CD44l°w) Thy1.1+ H2M−/− CD4 T cells into Rag−/− recipients, the current study aimed at investigating the role of TCR repertoire diversity during spontaneous proliferation and the subsequent development of chronic intestinal inflammation. We first noticed that H2M−/− CD4 T cell recipients rapidly lost body weight, even starting 7 days post transfer (Fig. 1A), which is in good contrast with WT T cell recipients that typically develop chronic colitis 4–6 weeks after the transfer [11]. Moreover, almost all H2M−/− CD4 T cell recipients succumb to death by 3 weeks post transfer (Fig. 1B). While we found no signs of gut inflammation in these groups of animals, we instead observed that the liver of H2M−/− T cell recipients showed severe necrotic lesion by both gross and histologic examinations (Fig. 1C). Histology demonstrated numerous portal thrombi composed of central cores of platelets and fibrin surrounded by neutrophils and mononuclear leukocytes (Fig. 1C, white arrowhead). In addition, moderate periportal inflammatory infiltrates of mononuclear cells and some neutrophils were evident with minimal bile duct damage. These inflammatory lesions were associated with extensive areas of coagulative necrosis characterized by eosinophilic cytoplasm and many pyknotic and karyorrhectic nuclei (Fig. 1C, black arrow). Other tissues including the intestine, kidney, and lung appeared to be intact (data not shown). The liver of WT CD4 T cell recipients showed no signs of liver necrosis even during severe intestinal inflammation (Fig. 1C and data not shown).


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

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

H2M−/− CD4 T cells induce severe necrotic inflammation in the liver.WT and H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (A) Weight loss and (B) survival were monitored after CD4 T cell transfer. Data are the mean ± SD of 4–9 individually tested animals from 2–3 independent experiments. (C) Liver picture and H&E stain of liver, (D) absolute number of donor CD4 T cells in different tissue, and (E) intracellular cytokine expression of the donor cells from the indicated tissues were determined 7 days post transfer. (F) Immunohistochemistry analysis of the CD3+ cells in the liver. Each symbol represents individually tested animals from two independent experiments. *, p<0.05; ***, p<0.001.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0110516-g001: H2M−/− CD4 T cells induce severe necrotic inflammation in the liver.WT and H2M−/− naïve CD4 T cells were adoptively transferred into Rag−/− recipients. (A) Weight loss and (B) survival were monitored after CD4 T cell transfer. Data are the mean ± SD of 4–9 individually tested animals from 2–3 independent experiments. (C) Liver picture and H&E stain of liver, (D) absolute number of donor CD4 T cells in different tissue, and (E) intracellular cytokine expression of the donor cells from the indicated tissues were determined 7 days post transfer. (F) Immunohistochemistry analysis of the CD3+ cells in the liver. Each symbol represents individually tested animals from two independent experiments. *, p<0.05; ***, p<0.001.
Mentions: When naïve CD4 T cells are transferred into severe lymphopenic hosts they undergo rapid spontaneous proliferation and develop into colitogenic effector cells producing IFNγ and/or IL-17 in response to antigens derived from commensal bacteria and self [2]. By transferring naïve phenotype (CD44l°w) Thy1.1+ H2M−/− CD4 T cells into Rag−/− recipients, the current study aimed at investigating the role of TCR repertoire diversity during spontaneous proliferation and the subsequent development of chronic intestinal inflammation. We first noticed that H2M−/− CD4 T cell recipients rapidly lost body weight, even starting 7 days post transfer (Fig. 1A), which is in good contrast with WT T cell recipients that typically develop chronic colitis 4–6 weeks after the transfer [11]. Moreover, almost all H2M−/− CD4 T cell recipients succumb to death by 3 weeks post transfer (Fig. 1B). While we found no signs of gut inflammation in these groups of animals, we instead observed that the liver of H2M−/− T cell recipients showed severe necrotic lesion by both gross and histologic examinations (Fig. 1C). Histology demonstrated numerous portal thrombi composed of central cores of platelets and fibrin surrounded by neutrophils and mononuclear leukocytes (Fig. 1C, white arrowhead). In addition, moderate periportal inflammatory infiltrates of mononuclear cells and some neutrophils were evident with minimal bile duct damage. These inflammatory lesions were associated with extensive areas of coagulative necrosis characterized by eosinophilic cytoplasm and many pyknotic and karyorrhectic nuclei (Fig. 1C, black arrow). Other tissues including the intestine, kidney, and lung appeared to be intact (data not shown). The liver of WT CD4 T cell recipients showed no signs of liver necrosis even during severe intestinal inflammation (Fig. 1C and data not shown).

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