289. Differential Activation of Innate Immune Responses and T Cell Proliferation by Adeno-Associated Virus Vectors Containing Different Regulatory Cassettes in Murine Pompe Disease

Allergic diseases, including atopic dermatitis (AD), induce type 2 helper T (Th2) cell-dominant immune responses. Miquelianin (quercetin 3-O-glucuronide, MQL) is an active compound in Rosae multiflorae fructus extract with anti-allergic properties. Here, we investigate the anti-allergic effects of MQL in an ovalbumin (OVA)-induced Th2-dominant mouse model and the associated mechanisms. Oral MQL suppressed cytokine and IL-2 production and proliferation of Th2 cells and upregulated heme oxygenase-1 (HO-1) in splenocytes. Ex vivo MQL suppressed Th1- and Th2-related immune responses by inhibiting CD4+ T cell proliferation, and upregulated HO-1 in CD4+ T cells by activating C-Raf–ERK1/2–Nrf2 pathway via induction of reactive oxygen species generation. In a trimellitic anhydride-induced AD-like mouse model, both topical and oral MQL ameliorated AD symptoms by suppressing Th2 immune responses. Our results suggest that MQL is a potential therapeutic agent for CD4+ T cell-mediated diseases, including allergic diseases.

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Expansion of Functional Myeloid-Derived Suppressor Cells in Controlled Human Malaria Infection

Frontiers in Immunology ◽

10.3389/fimmu.2021.625712 ◽

2021 ◽

Vol 12 ◽

Author(s):

Carlos Lamsfus Calle ◽

Rolf Fendel ◽

Anurag Singh ◽

Thomas L. Richie ◽

Stephen L. Hoffman ◽

...

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Malaria Infection ◽

Malaria Vaccine ◽

Suppressor Cells ◽

T Cell Proliferation ◽

Myeloid Derived Suppressor Cells ◽

Controlled Human Malaria Infection

Malaria can cause life-threatening complications which are often associated with inflammatory reactions. More subtle, but also contributing to the burden of disease are chronic, often subclinical infections, which result in conditions like anemia and immunologic hyporesponsiveness. Although very frequent, such infections are difficult to study in endemic regions because of interaction with concurrent infections and immune responses. In particular, knowledge about mechanisms of malaria-induced immunosuppression is scarce. We measured circulating immune cells by cytometry in healthy, malaria-naïve, adult volunteers undergoing controlled human malaria infection (CHMI) with a focus on potentially immunosuppressive cells. Infectious Plasmodium falciparum (Pf) sporozoites (SPZ) (PfSPZ Challenge) were inoculated during two independent studies to assess malaria vaccine efficacy. Volunteers were followed daily until parasites were detected in the circulation by RT-qPCR. This allowed us to analyze immune responses during pre-patency and at very low parasite densities in malaria-naïve healthy adults. We observed a consistent increase in circulating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in volunteers who developed P. falciparum blood stage parasitemia. The increase was independent of preceding vaccination with a pre-erythrocytic malaria vaccine. PMN-MDSC were functional, they suppressed CD4+ and CD8+ T cell proliferation as shown by ex-vivo co-cultivation with stimulated T cells. PMN-MDSC reduced T cell proliferation upon stimulation by about 50%. Interestingly, high circulating PMN-MDSC numbers were associated with lymphocytopenia. The number of circulating regulatory T cells (Treg) and monocytic MDSC (M-MDSC) showed no significant parasitemia-dependent variation. These results highlight PMN-MDSC in the peripheral circulation as an early indicator of infection during malaria. They suppress CD4+ and CD8+ T cell proliferation in vitro. Their contribution to immunosuppression in vivo in subclinical and uncomplicated malaria will be the subject of further research. Pre-emptive antimalarial pre-treatment of vaccinees to reverse malaria-associated PMN-MDSC immunosuppression could improve vaccine response in exposed individuals.

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Efficient costimulatory signal for T cell proliferation induced by human lymphoma cells transduced with B7-1 and B7-2 molecules by recombinant adeno-associated virus (AAV) vectors

European Journal of Cancer ◽

10.1016/0959-8049(95)99909-j ◽

1995 ◽

Vol 31 ◽

pp. S26

Author(s):

Elisabeth Mangold ◽

Clemens M. Wendtner ◽

Bertold Emmerich ◽

Ernst-Ludwig Winnacker ◽

Michael Hallek

Keyword(s):

Cell Proliferation ◽

T Cell ◽

T Cell Proliferation ◽

Lymphoma Cells ◽

Adeno Associated Virus ◽

Costimulatory Signal ◽

Human Lymphoma

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Enhanced IFN-γ, but not IL-2, response to Mycobacterium tuberculosis antigens in HIV/latent TB co-infected patients on long-term HAART

BMC Immunology ◽

10.1186/s12865-019-0317-9 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Girmay Desalegn ◽

Aster Tsegaye ◽

Dawit Gebreegziabiher ◽

Abraham Aseffa ◽

Rawleigh Howe

Keyword(s):

Cell Proliferation ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

Immune Responses ◽

T Cell Proliferation ◽

Median Frequency ◽

Immune Restoration ◽

Latent Tb ◽

Ifn Γ

Abstract Background HIV-infected individuals with latent TB infection are at increased risk of developing active TB. HAART greatly reduces the incidence rate of TB in HIV-infected patients and reconstitutes Mycobacterium tuberculosis (M. tuberculosis)-specific immune response in the first 12 months of therapy. The durability of the anti-mycobacterial immune restoration after a year of HAART however remains less investigated. Method A cross-sectional study was conducted to evaluate M. tuberculosis-specific functional immune responses in HIV/latent TB co-infected patients who were on HAART for at least 1.5 up to 9 years as compared to HAART-naïve patients. Three-hundred sixteen HIV-infected patients without active TB were screened by tuberculin skin testing for M. tuberculosis infection and peripheral blood mononuclear cells (PBMCs) were isolated from 61 HIV/latent TB co-infected patients (30 HAART-naïve and 31 HAART-treated). IFN-γ and IL-2 ELISPOT as well as CFSE cell proliferation assays were performed after stimulation with M. tuberculosis antigens PPD and ESAT-6. Result The median frequency of PPD and ESAT-6 specific IFN-γ secreting cells was significantly higher in the HAART-treated patients as compared to HAART-naïve patients, p = 0.0021 and p = 0.0081 respectively. However, there was no significant difference in the median frequency of IL-2 secreting cells responding to PPD (p = 0.5981) and ESAT-6 (p = 0.3943) antigens between HAART-naïve and-treated groups. Both IFN-γ and IL-2 responses were independent of CD4+ T cell count regardless of the HAART status. Notably, the frequency of PPD and ESAT-6 specific IL-2 secreting cells was positively associated with CD4+ T cell proliferation while inversely correlated with duration of HAART, raising the possibility that M. tuberculosis-specific IL-2 response that promote the antigen-specific CD4+ T cell proliferation diminish with time on antiretroviral therapy in HIV/latent TB co-infected patients. Conclusion This study shows an increased M. tuberculosis-specific IFN-γ, but not IL-2, response in HIV/latent TB co-infected patients with long-term HAART, consistent with only partial immune restoration. Future studies should, therefore, be done to prospectively define the rate and extent to which functional immune responses to M. tuberculosis are restored after long-term HAART.

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Interleukin-27 Is a Potential Rescue Therapy for Acute Severe Colitis Through Interleukin-10–Dependent, T-Cell–Independent Attenuation of Colonic Mucosal Innate Immune Responses

Inflammatory Bowel Diseases ◽

10.1097/mib.0000000000001274 ◽

2017 ◽

Vol 23 (11) ◽

pp. 1983-1995 ◽

Cited By ~ 8

Author(s):

Mairi H. McLean ◽

Caroline Andrews ◽

Miranda L. Hanson ◽

Walter A. Baseler ◽

Miriam R. Anver ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Rescue Therapy ◽

Interleukin 10 ◽

Innate Immune ◽

Innate Immune Responses ◽

Interleukin 27 ◽

Acute Severe Colitis ◽

Severe Colitis

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The guinea pig I region. II. Functional analysis.

Journal of Experimental Medicine ◽

10.1084/jem.146.2.561 ◽

1977 ◽

Vol 146 (2) ◽

pp. 561-570 ◽

Cited By ~ 20

Author(s):

E M Shevach ◽

M L Lundquist ◽

A F Geczy ◽

B D Schwartz

Keyword(s):

Functional Analysis ◽

Cell Proliferation ◽

T Cell ◽

Immune Responses ◽

Guinea Pig ◽

T Cell Proliferation ◽

Ia Antigen ◽

Ia Antigens ◽

Region Ii ◽

Ir Genes

We have examined whether an association exists between specific Ia antigen genes and Ir genes which are encoded within the same haplotype. Functionally monospecific sera to the Ia antigens of the guinea pig MHC were selective in their ability to inhibit antigen-specific T-cell proliferation and we were thus able to demonstrate an association between individual Ia specificities and specific Ir genes. The results of these studies in inbred animals were confirmed by examining the association of Ir genes and Ia antigens in the outbred guinea pig population. Of great interest was the observation that antisera made against cross-reactive Ia antigens of strains lacking specific Ir genes would still inhibit immune responses of strains possessing the Ir gene, if the Ir gene was associated with that Ia antigen in the responder strain.

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Decoding the role of CBLB for innate immune responses regulating systemic dissemination during Non-Tuberculous Mycobacteria infection

10.1101/2020.05.28.117663 ◽

2020 ◽

Author(s):

Srinivasu Mudalagiriyappa ◽

Jaishree Sharma ◽

Hazem F. M. Abdelaal ◽

Thomas C. Kelly ◽

Woosuk Choi ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Granulomatous Inflammation ◽

Innate Immune ◽

Dependent Manner ◽

Innate Immune Responses ◽

Inflammatory Monocytes ◽

Cell Immunity

AbstractNon-Tuberculous Mycobacteria (NTM) are ubiquitous in nature, present in soil and water, and cause primary leading to disseminated infections in immunocompromised individuals. NTM infections are surging in recent years due to an increase in an immune-suppressed population, medical interventions, and patients with underlying lung diseases. Host regulators of innate immune responses, frontiers for controlling infections and dissemination, are poorly defined during NTM infections. Here, we describe the role of CBLB, an E3-ubiquitin ligase, for innate immune responses and disease progression in a mouse model of NTM infection under compromised T-cell immunity. We found that CBLB thwarted NTM growth and dissemination in a time- and infection route- dependent manner. Mechanistically, we uncovered defects in many innate immune cells in the absence of Cblb, including poor responses of NK cells, inflammatory monocytes, and conventional dendritic cells. Strikingly, Cblb-deficient macrophages were competent to control NTM growth in vitro. Histopathology suggested the lack of early formation of granulomatous inflammation in the absence of CBLB. Collectively, CBLB is essential to mount productive innate immune responses and help prevent the dissemination during an NTM infection under T-cell deficiency.

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