IFN-γ Control of an Effector/Target Combination for Skin Allograft Rejection: Macrophage/Skin Components in Normal Mice or T Cell/Endothelial Cells in IFN-γ-Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

Download Full-text

T cell-dependent immune response in C1q deficient mice: Defective IFN-γ production by antigen-specific T cells

Molecular Immunology ◽

10.1016/s0161-5890(98)90587-9 ◽

1998 ◽

Vol 35 (6-7) ◽

pp. 344 ◽

Cited By ~ 1

Author(s):

A.J. Cutler ◽

M. Botto ◽

D. van Essen ◽

K.A. Davies ◽

D. Gray ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Ifn Γ ◽

Deficient Mice

Download Full-text

THE CD4+ EFFECTOR T CELL REQUIRES IFN-γ TO MEDIATE ACUTE CARDIAC ALLOGRAFT REJECTION

Transplantation Journal ◽

10.1097/00007890-199904150-00089 ◽

1999 ◽

Vol 67 (7) ◽

pp. S22

Author(s):

A. C. Wiseman ◽

B. A. Pietra ◽

M. A. Rizeq ◽

R. G. Gill

Keyword(s):

T Cell ◽

Allograft Rejection ◽

Cardiac Allograft ◽

Cardiac Allograft Rejection ◽

Effector T Cell ◽

Ifn Γ

Download Full-text

Cytotoxic T Lymphocyte Antigen 4 (CTLA4) Blockade Accelerates the Acute Rejection of Cardiac Allografts in CD28-deficient Mice: CTLA4 Can Function Independently of CD28

Journal of Experimental Medicine ◽

10.1084/jem.188.1.199 ◽

1998 ◽

Vol 188 (1) ◽

pp. 199-204 ◽

Cited By ~ 143

Author(s):

Hua Lin ◽

Jeffrey C. Rathmell ◽

Gary S. Gray ◽

Craig B. Thompson ◽

Jeffrey M. Leiden ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

T Lymphocyte ◽

Graft Rejection ◽

Allograft Rejection ◽

Cell Activation ◽

Cytotoxic T Lymphocyte ◽

Wild Type ◽

Lymphocyte Antigen ◽

Deficient Mice

Cytotoxic T lymphocyte antigen 4 (CTLA4) appears to negatively regulate T cell activation. One mechanism by which CTLA4 might antagonize T cell function is through inhibition of CD28 signaling by competing for their shared ligands B7-1 and B7-2. In addition, CTLA4 ligation could initiate a signaling cascade that inhibits T cell activation. To address whether CTLA4 could inhibit immune responses in the absence of CD28, rejection of heart allografts was studied in CD28-deficient mice. H-2q hearts were transplanted into allogeneic wild-type or CD28-deficient mice (H-2b). Graft rejection was delayed in CD28-deficient compared with wild-type mice. Treatment of wild-type recipients with CTLA4-immunoglobulin (Ig), or with anti–B7-1 plus anti–B7-2 mAbs significantly prolonged allograft survival. In contrast, treatment of CD28-deficient mice with CTLA4-Ig, anti–B7-1 plus anti–B7-2 mAbs, or a blocking anti-CTLA4 mAb induced acceleration of allograft rejection. This increased rate of graft rejection was associated with more severe mononuclear cell infiltration and enhanced levels of IFN-γ and IL-6 transcripts in donor hearts of untreated wild-type and CTLA4-Ig– or anti-CTLA4 mAb–treated CD28-deficient mice. Thus, the negative regulatory role of CTLA4 extends beyond its potential ability to prevent CD28 activation through ligand competition. Even in the absence of CD28, CTLA4 plays an inhibitory role in the regulation of allograft rejection.

Download Full-text

Evidence for a role of IFN γ in control ofListeria monocytogenes in T cell deficient mice

Cellular and Molecular Life Sciences ◽

10.1007/bf01949893 ◽

1991 ◽

Vol 47 (6) ◽

pp. 630-632 ◽

Cited By ~ 1

Author(s):

T. P. Leist ◽

A. Meager ◽

T. Exley ◽

R. M. Zinkernagel

Keyword(s):

T Cell ◽

Ifn Γ ◽

Oflisteria Monocytogenes ◽

Deficient Mice

Download Full-text

Perforin and Gamma Interferon Are Critical CD8+ T-Cell-Mediated Responses in Vaccine-Induced Immunity against Leishmania amazonensis Infection

Infection and Immunity ◽

10.1128/iai.71.6.3172-3182.2003 ◽

2003 ◽

Vol 71 (6) ◽

pp. 3172-3182 ◽

Cited By ~ 56

Author(s):

María Colmenares ◽

Peter E. Kima ◽

Erika Samoff ◽

Lynn Soong ◽

Diane McMahon-Pratt

Keyword(s):

T Cells ◽

T Cell ◽

Cell Subset ◽

Protective Role ◽

Gamma Interferon ◽

Leishmania Amazonensis ◽

Immunological Mechanisms ◽

Ifn Γ ◽

Deficient Mice ◽

Effector Mechanisms

ABSTRACT Previous studies have demonstrated that protection against New World leishmaniasis caused by Leishmania amazonensis can be elicited by immunization with the developmentally regulated Leishmania amastigote antigen, P-8. In this study, several independent experimental approaches were employed to investigate the protective immunological mechanisms involved. T-cell subset depletion experiments clearly indicate that elicitation of CD8+ (as well as CD4+) effector responses is required for protection. Further, mice lacking β2-microglobulin (and hence deficient in major histocompatibility complex class I antigen presentation) were not able to control a challenge infection after vaccination, indicating an essential protective role for CD8+ T effector responses. Analysis of the events ongoing at the cutaneous site of infection indicated a changing cellular dynamic involved in protection. Early postinfection in protectively vaccinated mice, a predominance of CD8+ T cells, secreting gamma interferon (IFN-γ) and expressing perforin, was observed at the site of infection; subsequently, activated CD4+ T cells producing IFN-γ were primarily found. As protection correlated with the ratio of total IFN-γ-producing cells (CD4+ and CD8+ T cells) to macrophages found at the site of infection, a role for IFN-γ was evident; in addition, vaccination of IFN-γ-deficient mice failed to provide protection. To further assess the effector mechanisms that mediate protection, mice deficient in perforin synthesis were examined. Perforin-deficient mice vaccinated with the P-8 antigen were unable to control infection. Thus, the elicitation of CD8+ T cell effector mechanisms (perforin, IFN-γ) are clearly required in the protective immune response against L. amazonensis infection in vaccinated mice.

Download Full-text

Modulation of LIGHT-HVEM Costimulation Prolongs Cardiac Allograft Survival

Journal of Experimental Medicine ◽

10.1084/jem.20012088 ◽

2002 ◽

Vol 195 (6) ◽

pp. 795-800 ◽

Cited By ~ 94

Author(s):

Qunrui Ye ◽

Christopher C. Fraser ◽

Wei Gao ◽

Liqing Wang ◽

Samantha J. Busfield ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Allograft Rejection ◽

Cell Activation ◽

Cardiac Allograft ◽

Allograft Survival ◽

Activated T Cells ◽

Cardiac Allograft Rejection ◽

Ifn Γ

LIGHT (TNFSF14), a tumor necrosis factor superfamily member expressed by activated T cells, binds to herpes virus entry mediator (HVEM) which is constitutively expressed by T cells and costimulates T cell activation in a CD28-independent manner. Given interest in regulating the effector functions of T cells in vivo, we examined the role of LIGHT-HVEM costimulation in a murine cardiac allograft rejection model. Normal hearts lacked LIGHT or HVEM mRNA expression, but allografts showed strong expression of both genes from day 3 after transplant, and in situ hybridization and immunohistology-localized LIGHT and HVEM to infiltrating leukocytes. To test the importance of LIGHT expression on allograft survival, we generated LIGHT−/− mice by homologous recombination. The mean survival of fully major histocompatibility complex–mismatched vascularized cardiac allografts in LIGHT−/− mice (10 days, P < 0.05) or cyclosporine A (CsA)-treated LIGHT+/+ mice (10 days, P < 0.05) was only slightly prolonged compared with LIGHT+/+ mice (7 days). However, mean allograft survival in CsA-treated LIGHT−/− allograft recipients (30 days) was considerably enhanced (P < 0.001) compared with the 10 days of mean survival in either untreated LIGHT−/− mice or CsA-treated LIGHT+/+ controls. Molecular analyzes showed that the beneficial effects of targeting of LIGHT in CsA-treated recipients were accompanied by decreased intragraft expression of interferon (IFN)-γ, plus IFN-γ–induced chemokine, inducible protein-10, and its receptor, CXCR3. Treatment of LIGHT+/+ allograft recipients with HVEM-Ig plus CsA also enhanced mean allograft survival (21 days) versus wild-type controls receiving HVEM-Ig (mean of 7 days) or CsA alone (P < 0.001). Our data suggest that T cell to T cell–mediated LIGHT/HVEM-dependent costimulation is a significant component of the host response leading to cardiac allograft rejection.

Download Full-text

Requirement of the Chemokine Receptor CXCR3 for Acute Allograft Rejection

Journal of Experimental Medicine ◽

10.1084/jem.192.10.1515 ◽

2000 ◽

Vol 192 (10) ◽

pp. 1515-1520 ◽

Cited By ~ 487

Author(s):

Wayne W. Hancock ◽

Bao Lu ◽

Wei Gao ◽

Vilmos Csizmadia ◽

Kerrie Faia ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Chemokine Receptor ◽

Allograft Rejection ◽

Cell Activation ◽

Acute Allograft Rejection ◽

Activated T Cells ◽

In Vivo Models ◽

Ifn Γ

Chemokines provide signals for activation and recruitment of effector cells into sites of inflammation, acting via specific G protein–coupled receptors. However, in vitro data demonstrating the presence of multiple ligands for a given chemokine receptor, and often multiple receptors for a given chemokine, have led to concerns of biologic redundancy. Here we show that acute cardiac allograft rejection is accompanied by progressive intragraft production of the chemokines interferon (IFN)-γ–inducible protein of 10 kD (IP-10), monokine induced by IFN-γ (Mig), and IFN-inducible T cell α chemoattractant (I-TAC), and by infiltration of activated T cells bearing the corresponding chemokine receptor, CXCR3. We used three in vivo models to demonstrate a role for CXCR3 in the development of transplant rejection. First, CXCR3-deficient (CXCR3−/−) mice showed profound resistance to development of acute allograft rejection. Second, CXCR3−/− allograft recipients treated with a brief, subtherapeutic course of cyclosporin A maintained their allografts permanently and without evidence of chronic rejection. Third, CXCR+/+ mice treated with an anti-CXCR3 monoclonal antibody showed prolongation of allograft survival, even if begun after the onset of rejection. Taken in conjunction with our findings of CXCR3 expression in rejecting human cardiac allografts, we conclude that CXCR3 plays a key role in T cell activation, recruitment, and allograft destruction.

Download Full-text

T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with DisseminatedChlamydia muridarumGenital Tract Infection

Infection and Immunity ◽

10.1128/iai.00143-18 ◽

2018 ◽

Vol 86 (7) ◽

pp. e00143-18 ◽

Cited By ~ 6

Author(s):

Taylor B. Poston ◽

Catherine M. O'Connell ◽

Jenna Girardi ◽

Jeanne E. Sullivan ◽

Uma M. Nagarajan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

Tract Infection ◽

B Cell ◽

Gamma Interferon ◽

Wild Type ◽

Content Type ◽

Ifn Γ ◽

Deficient Mice

ABSTRACTCD4 T cells and antibody are required for optimal acquired immunity toChlamydia muridarumgenital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice withC. muridarumCM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal forSTAT1−/−andIFNG−/−mice, in which IFN-γ signaling was absent, and forRag1−/−mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM toRag1−/−mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescuedRag1−/−mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

Download Full-text

The Antiviral Efficacy of the Murine Alpha-1 Interferon Transgene against Ocular Herpes Simplex Virus Type 1 Requires the Presence of CD4+, α/β T-Cell Receptor-Positive T Lymphocytes with the Capacity To Produce Gamma Interferon

Journal of Virology ◽

10.1128/jvi.76.18.9398-9406.2002 ◽

2002 ◽

Vol 76 (18) ◽

pp. 9398-9406 ◽

Cited By ~ 15

Author(s):

Daniel J. J. Carr ◽

Sansanee Noisakran

Keyword(s):

T Cell ◽

Plasmid Vector ◽

Cell Receptor ◽

Wild Type ◽

Targeted Disruption ◽

Ifn Γ ◽

Simplex Virus ◽

Deficient Mice ◽

Hsv 1

ABSTRACT Alpha/beta interferons (IFN-α/βs) are known to antagonize herpes simplex virus type 1 (HSV-1) infection by directly blocking viral replication and promoting additional innate and adaptive, antiviral immune responses. To further define the relationship between the adaptive immune response and IFN-α/β, the protective effect induced following the topical application of plasmid DNA containing the murine IFN-α1 transgene onto the corneas of wild-type and T-cell-deficient mice was evaluated. Mice homozygous for both the T-cell receptor (TCR) β- and δ-targeted mutations expressing no αβ or γδ TCR (αβ/γδ TCR double knockout [dKO]) treated with the IFN-α1 transgene succumbed to ocular HSV-1 infection at a rate similar to that of αβ/γδ TCR dKO mice treated with the plasmid vector DNA. Conversely, mice with targeted disruption of the TCR δ chain and expressing no γδ TCR+ cells treated with the IFN-α1 transgene survived the infection to a greater extent than the plasmid vector-treated counterpart and at a level similar to that of wild-type controls treated with the IFN-α1 transgene. By comparison, mice with targeted disruption of the TCR β chain and expressing no αβ TCR+ cells (αβ TCR knockout [KO]) showed no difference upon treatment with the IFN-α1 transgene or the plasmid vector control, with 0% survival following HSV-1 infection. Adoptively transferring CD4+ but not CD8+ T cells from wild-type but not IFN-γ-deficient mice reestablished the antiviral efficacy of the IFN-α1 transgene in αβ TCR KO mice. Collectively, the results indicate that the protective effect mediated by topical application of a plasmid construct containing the murine IFN-α1 transgene requires the presence of CD4+ T cells capable of IFN-γ synthesis.

Download Full-text