Leishmania donovani p36(LACK) DNA Vaccine Is Highly Immunogenic but Not Protective against Experimental Visceral Leishmaniasis

ABSTRACT The acquisition of immunity following subclinical or resolved infection with the intracellular parasite Leishmania donovani suggests that vaccination could prevent visceral leishmaniasis (VL). The LACK (Leishmania homolog of receptors for activated C kinase) antigen is of interest as a vaccine candidate for the leishmaniases because of its immunopathogenic role in murine L. major infection. Immunization of mice with a truncated (24-kDa) version of the 36-kDa LACK antigen, delivered in either protein or DNA form, was found previously to protect against cutaneous L. major infection by redirecting the early T-cell response away from a pathogenic interleukin-4 (IL-4) response and toward a protective Th1 response. The amino acid sequence of theLeishmania p36(LACK) antigen is highly conserved, but the efficacy of this vaccine antigen in preventing disease caused by strains other than L. major has not been determined. We investigated the efficacy of a p36(LACK) DNA vaccine against VL because of the serious nature of this form of leishmaniasis and because it was unclear whether the LACK vaccine would be effective in a model where there was not a dominant pathogenic IL-4 response. We demonstrate here that although the LACK DNA vaccine induced a robust parasite-specific Th1 immune response (IFN-γ but not IL-4 production) and primed for an in vivo T-cell response to inoculated parasites, it did not induce protection against cutaneous or systemic L. donovanichallenge. Coadministration of IL-12 DNA with the vaccine did not enhance the strong vaccine-induced Th1 response or augment a protective effect.

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Leishmania donovani skews the CD56+ Natural Killer T cell response during human visceral leishmaniasis

Cytokine ◽

10.1016/j.cyto.2015.01.011 ◽

2015 ◽

Vol 73 (1) ◽

pp. 53-60 ◽

Cited By ~ 9

Author(s):

Sarita Kumari ◽

Fauzia Jamal ◽

Pushkar Shivam ◽

Ajit Thakur ◽

Manish Kumar ◽

...

Keyword(s):

T Cell ◽

Visceral Leishmaniasis ◽

Natural Killer ◽

Cell Response ◽

Leishmania Donovani ◽

T Cell Response ◽

Natural Killer T Cell ◽

Human Visceral Leishmaniasis ◽

Killer T Cell ◽

Natural Killer T

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Induction of T-cell response by a DNA vaccine encoding a novel HLA-A*0201 severe acute respiratory syndrome coronavirus epitope

Vaccine ◽

10.1016/j.vaccine.2007.05.025 ◽

2007 ◽

Vol 25 (32) ◽

pp. 6070-6077 ◽

Cited By ~ 32

Author(s):

Ying-Kit Cheung ◽

Samuel Chak-Sum Cheng ◽

Fion Wan-Yee Sin ◽

Kin-Tak Chan ◽

Yong Xie

Keyword(s):

T Cell ◽

Severe Acute Respiratory Syndrome ◽

Dna Vaccine ◽

Cell Response ◽

T Cell Response

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A Switch in Costimulation from CD28 to 4-1BB during Primary versus Secondary CD8 T Cell Response to Influenza In Vivo

The Journal of Immunology ◽

10.4049/jimmunol.172.2.981 ◽

2004 ◽

Vol 172 (2) ◽

pp. 981-988 ◽

Cited By ~ 98

Author(s):

Edward M. Bertram ◽

Wojciech Dawicki ◽

Bradley Sedgmen ◽

Jonathan L. Bramson ◽

David H. Lynch ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Cd8 T Cell ◽

T Cell Response

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PD-L1hi plasmablasts limit the T cell response during the acute phase of parasite infections

10.1101/2020.06.10.142067 ◽

2020 ◽

Author(s):

Melisa Gorosito Serrán ◽

Facundo Fiocca Vernengo ◽

Laura Almada ◽

Cristian G Beccaria ◽

Pablo F Canete ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Cell Activation ◽

Mononuclear Cells ◽

Plasma Cells ◽

Chronic Phase ◽

Surface Expression ◽

T Cell Response

ABSTRACTDuring infections with protozoan parasites or virus, T cell immunosuppression is generated simultaneously with a high B cell activation. Here, we show that in T. cruzi infection, all plasmablasts detected had higher surface expression of PD-L1, than other mononuclear cells. PD-L1hi plasmablasts were induced in vivo in an antigen-specific manner and required help from Bcl-6+CD4+T cells. PD-L1hi expression was not a characteristic of all antibody-secreting cells since plasma cells found during the chronic phase of infection express PD-L1 but at lower levels. PD-L1hi plasmablasts were also present in mice infected with Plasmodium or with lymphocytic choriomeningitis virus, but not in mice with autoimmune disorders or immunized with T cell-dependent antigens. PD-L1hi plasmablasts suppressed T cell response, via PD-L1, in vitro and in vivo. Thus, this study reveals that extrafollicular PD-L1hi plasmablasts, which precede the germinal center (CG) response, are a suppressive population in infections that may influence T cell response.Brief summaryPathogens develop different strategies to settle in the host. We identified a plasmablats population induced by pathogens in acute infections which suppress T cell response.

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In vivo splenic CD11c cells downregulate CD4 T-cell response thereby decreasing systemic immunity to gene-modified tumour cell vaccine

Gene Therapy ◽

10.1038/sj.gt.3303003 ◽

2007 ◽

Vol 14 (20) ◽

pp. 1481-1491

Author(s):

S Cayeux ◽

B Bukarica ◽

C Buschow ◽

J Charo ◽

M Bunse ◽

...

Keyword(s):

T Cell ◽

Tumour Cell ◽

Cell Response ◽

T Cell Response ◽

Cd4 T Cell ◽

Cell Vaccine ◽

Systemic Immunity

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Acidosis-Induced TGF-β2 Production Promotes Lipid Droplet Formation in Dendritic Cells and Alters Their Potential to Support Anti-Mesothelioma T Cell Response

Cancers ◽

10.3390/cancers12051284 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1284

Author(s):

Natalia Trempolec ◽

Charline Degavre ◽

Bastien Doix ◽

Davide Brusa ◽

Cyril Corbet ◽

...

Keyword(s):

Dendritic Cells ◽

T Cell ◽

Lipid Droplet ◽

T Cell Activation ◽

Cell Response ◽

Cell Activation ◽

Transforming Growth Factor ◽

T Cell Response ◽

Mesenchymal Transition

For poorly immunogenic tumors such as mesothelioma there is an imperious need to understand why antigen-presenting cells such as dendritic cells (DCs) are not prone to supporting the anticancer T cell response. The tumor microenvironment (TME) is thought to be a major contributor to this DC dysfunction. We have reported that the acidic TME component promotes lipid droplet (LD) formation together with epithelial-to-mesenchymal transition in cancer cells through autocrine transforming growth factor-β2 (TGF-β2) signaling. Since TGF-β is also a master regulator of immune tolerance, we have here examined whether acidosis can impede immunostimulatory DC activity. We have found that exposure of mesothelioma cells to acidosis promotes TGF-β2 secretion, which in turn leads to LD accumulation and profound metabolic rewiring in DCs. We have further documented how DCs exposed to the mesothelioma acidic milieu make the anticancer vaccine less efficient in vivo, with a reduced extent of both DC migratory potential and T cell activation. Interestingly, inhibition of TGF-β2 signaling and diacylglycerol O-acyltransferase (DGAT), the last enzyme involved in triglyceride synthesis, led to a significant restoration of DC activity and anticancer immune response. In conclusion, our study has identified that acidic mesothelioma milieu drives DC dysfunction and altered T cell response through pharmacologically reversible TGF-β2-dependent mechanisms.

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