Dataset Information

Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection.

ABSTRACT: Although induction of CD8 T-cell responses to transplants requires CD4-cell help, how this help is transmitted remains incompletely characterized. In vitro, cognate interactions between CD4 T cells and dendritic cells (DCs) induce C3a and C5a production. CD8(+) T cells lacking C3a receptor (C3aR) and C5a receptor (C5aR) proliferate weakly to allogeneic DCs despite CD4 help, indicating that CD4-cell help is mediated, in part, through DC-derived C3a/C5a acting on CD8(+) T cell-expressed C3aR/C5aR. In support of this concept, augmenting DC C5a/C3a production bypasses the requirement for CD4- and CD40-dependent help to wild-type CD8(+) T cells. CD4-deficient recipients of allogeneic heart transplants prime weak CD8 responses and do not acutely reject their grafts. In contrast, CD4-deficient chimeric mice possessing decay accelerating factor deficient (Daf1(-/-)) bone marrow, in which DC C3a/C5a production is potentiated, acutely reject transplants through a CD8 cell-dependent mechanism. Furthermore, hearts transplanted into CD40(-/-) mice prime weak CD8-cell responses and survive indefinitely, but hearts transplanted into Daf1(-/-)CD40(-/-) recipients undergo CD8 cell-dependent rejection. Together, the data indicate that heightened production and activation of immune cell-derived complement bypasses the need for CD40/CD154 interactions and implicate antigen-presenting cell-produced C5a and C3a as molecular bridges linking CD4 help to CD8(+) T cells.

SUBMITTER: Vieyra M

PROVIDER: S-EPMC3157191 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection.

Vieyra Mark M Leisman Staci S Raedler Hugo H Kwan Wing-Hong WH Yang Min M Strainic Michael G MG Medof M Edward ME Heeger Peter S PS

The American journal of pathology 20110623 2

Although induction of CD8 T-cell responses to transplants requires CD4-cell help, how this help is transmitted remains incompletely characterized. In vitro, cognate interactions between CD4 T cells and dendritic cells (DCs) induce C3a and C5a production. CD8(+) T cells lacking C3a receptor (C3aR) and C5a receptor (C5aR) proliferate weakly to allogeneic DCs despite CD4 help, indicating that CD4-cell help is mediated, in part, through DC-derived C3a/C5a acting on CD8(+) T cell-expressed C3aR/C5aR. ...[more]

PMID: 21704012

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Project description:Due to vigorous alloimmunity, an allograft is usually rejected without any conventional immunosuppressive treatment. However, continuous global immunosuppression may cause severe side effects, including tumors and infections. Mounting evidence has shown that cyclosporine (CsA), a common immunosuppressant used in clinic, impedes allograft tolerance by dampening regulatory T cells (Tregs), although it inhibits allograft rejection at the same time. Therefore, it is necessary to seek an alternative immunosuppressive drug that spares Tregs with high efficiency in suppression but low toxicity. In this study, we investigated the capacity of emodin, an anthraquinone molecule originally extracted from certain natural plants, to prolong transplant survival in a mouse model and explored the cellular and molecular mechanisms underlying its action. We found that emodin significantly extended skin allograft survival and hindered CD3+ T cell infiltration in the allograft, accompanied by an increase in CD4+Foxp3+ and CD8+CD122+ Treg frequencies and numbers but a reduction in effector CD8+CD44highCD62Llow T cells in recipient mice. Emodin also inhibited effector CD8+ T cells proliferation in vivo. However, CD4+CD25+, but not CD8+CD122+, Tregs derived from emodin-treated recipients were more potent in suppression of allograft rejection than those isolated from control recipients, suggesting that emodin also enhances the suppressive function of CD4+CD25+ Tregs. Interestingly, depleting CD25+ Tregs largely reversed skin allograft survival prolonged by emodin while depleting CD122+ Tregs only partially abrogated the same allograft survival. Furthermore, we found that emodin hindered dendritic cell (DC) maturation and reduced alloantibody production posttransplantation. Finally, we demonstrated that emodin inhibited in vitro proliferation of T cells and blocked their mTOR signaling as well. Therefore, emodin may be a novel mTOR inhibitor that suppresses alloimmunity by inducing both CD4+FoxP3+ and CD8+CD122+ Tregs, suppressing alloantibody production, and hindering DC maturation. Thus, emodin is a newly emerging immunosuppressant and could be utilized in clinical transplantation in the future.

Project description:Low levels of plasma adiponectin, an adipocytokine that possesses anti-inflammatory and antiatherogenic properties, frequently observed among obese subjects correlate with higher prevalence of several cardiovascular diseases. This study investigated whether adiponectin modulates allograft rejection in major histocompatibility complex class II-mismatched cardiac transplants.We heterotopically transplanted Bm12 allografts into adiponectin-deficient (APN-/-, C57BL/6 background) or wild-type (APN+/+) mice. Some APN-/- mice received adiponectin reconstitution by adenovirus. Histologic analyses assessed allograft rejection, and real-time reverse-transcriptase polymerase chain reaction evaluated the genes for cytokines/chemokines associated with the immune and inflammatory responses. In addition, we tested the effect of adiponectin on proliferation and cytokine/chemokine production in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.Allografts transplanted to APN-/- mice showed severe acute rejection relative to transplants in APN+/+ hosts accompanied by increased accumulation of CD4- and CD8-positive T lymphocytes and Mac3-positive macrophages. Adiponectin provision by adenovirus in APN-/- mice reversed these exacerbated responses to allografting. The rejected allografts in APN-/- mice contained significantly higher levels of tumor necrosis factor-alpha, interferon-gamma, and regulated on activation normal t expressed and presumably secreted. Moreover, adiponectin significantly suppressed proliferation and production of tumor necrosis factor-alpha, interferon-gamma, regulated on activation normal t expressed and presumably secreted, monocyte chemotactic protein-1, and interferon-gamma inducible protein-10 in mouse T lymphocytes stimulated in vitro with anti-CD3 antibodies.These observations provide new mechanistic insight into immunoregulation in allograft recipients relative to obesity, an increasingly prevalent risk factor. Adiponectin may offer a new therapeutic target for allograft rejection after cardiac transplantation.

Dataset Information

Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection.

Publications

Complement regulates CD4 T-cell help to CD8 T cells required for murine allograft rejection.

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