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Centrin-Deleted Leishmania donovani Parasites Help CD4 + T Cells to Acquire Th1 Phenotype and Multi-Functionality Through Downregulation of CD200-CD200R Immune Inhibitory Axis.
- Source :
-
Frontiers in immunology [Front Immunol] 2018 Jun 04; Vol. 9, pp. 1176. Date of Electronic Publication: 2018 Jun 04 (Print Publication: 2018). - Publication Year :
- 2018
-
Abstract
- The protozoan parasite Leishmania has evolved several strategies to undermine host defense mechanisms by inducing Th2-type adaptive immunity and suppressing effector functions of Th1 phenotype. In our earlier studies, using centrin gene-deleted Leishmania (LdCen <superscript>-/-</superscript> ) parasites as an immunogen, we have shown induction of an effective Th1-type immunity and robust memory responses that mediate protection against virulent challenge. However, role of inhibitory signals in Leishmania vaccine induced immunity in general, and LdCen <superscript>-/-</superscript> in particular has not been studied. Herein, we report that immunization with LdCen <superscript>-/-</superscript> parasites produces more functional Th1-type CD4 <superscript>+</superscript> T cells via downregulation of CD200-CD200R immune inhibitory axis compared to wild-type infection. We found that expression of CD200 and CD200R was significantly reduced in LdCen <superscript>-/-</superscript> infection compared to wild-type infection. Diminished CD200-CD200R signaling in LdCen <superscript>-/-</superscript> infection enabled proliferation of CD4 <superscript>+</superscript> T cells and resulted in the induction of pro-inflammatory cytokines and suppression of anti-inflammatory response. The effects of diminished CD200-CD200R signaling by LdCen <superscript>-/-</superscript> were most evident in the suppression of IL-10-producing CD4 <superscript>+</superscript> T cells that helped enhance more Th1 cytokine producing and multi-functional T cells compared to wild-type infection. In vivo blocking of CD200 expression with anti-CD200 treatment in wild-type infected mice limited Th2 response as indicated by reduction of IL-10-producing Tr1 cells and reduced parasite burden. On the other hand, treatment with anti-CD200 improved the LdCen <superscript>-/-</superscript> vaccine-induced multifunctional response and reduction in splenic parasite load upon challenge. Taken together, these studies demonstrate the role of CD200-CD200R signals in the protection induced by LdCen <superscript>-/-</superscript> parasites.
- Subjects :
- Animals
Antigens, CD metabolism
Antigens, Protozoan genetics
CD4 Antigens metabolism
Calcium-Binding Proteins genetics
Cell Differentiation
Chromosomal Proteins, Non-Histone genetics
Down-Regulation
Female
Gene Knockout Techniques
Humans
Immunophenotyping
Lymphocyte Activation
Membrane Glycoproteins metabolism
Mice
Mice, Inbred C57BL
Microorganisms, Genetically-Modified
Signal Transduction
Antigens, Protozoan metabolism
Calcium-Binding Proteins metabolism
Chromosomal Proteins, Non-Histone metabolism
Leishmania donovani physiology
Leishmaniasis, Visceral immunology
Th1 Cells immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1664-3224
- Volume :
- 9
- Database :
- MEDLINE
- Journal :
- Frontiers in immunology
- Publication Type :
- Academic Journal
- Accession number :
- 29915577
- Full Text :
- https://doi.org/10.3389/fimmu.2018.01176