TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion
Toll like receptor 4 (TLR4) is an important pattern recognition receptor with the ability to drive potent innate immune responses and also to modulate adaptive immune responses needed for long term protection. Activation of TLR4 by its ligands is mediated by engagement of the adapter proteins MyD88...
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Public Library of Science
2013
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574014/ |
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pubmed-35740142013-03-01 TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion Gandhapudi, Siva K. Chilton, Paula M. Mitchell, Thomas C. Research Article Toll like receptor 4 (TLR4) is an important pattern recognition receptor with the ability to drive potent innate immune responses and also to modulate adaptive immune responses needed for long term protection. Activation of TLR4 by its ligands is mediated by engagement of the adapter proteins MyD88 (myeloid differentiation factor 88) and TRIF (Toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta). Previously, we showed that TRIF, but not MyD88, plays an important role in allowing TLR4 agonists to adjuvant early T cell responses. In this study, we investigated the T cell priming events that are regulated specifically by the TRIF signaling branch of TLR4. We found that TRIF deficiency prevented the TLR4 agonist lipid A from enhancing T cell proliferation and survival in an adoptive transfer model of T cell priming. TRIF deficient DC showed defective maturation as evidenced by their failure to upregulate co-stimulatory molecules in response to lipid A stimulation. Importantly, TRIF alone caused CD86 and CD40 upregulation on splenic DC, but both TRIF and MyD88 were required for CD80 upregulation. The impairment of T cell adjuvant effects and defective DC maturation in TRIF lps/lps mice after TLR4 stimulation was mainly due to loss of type I IFN production, indicating that type I interferons are central to TLR4's adjuvant effects. These results are useful for the continued development of TLR4 based vaccine adjuvants that avoid inflammatory risks while retaining beneficial immune response. Public Library of Science 2013-02-15 /pmc/articles/PMC3574014/ /pubmed/23457630 http://dx.doi.org/10.1371/journal.pone.0056855 Text en https://creativecommons.org/publicdomain/zero/1.0/ This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration, which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Gandhapudi, Siva K. Chilton, Paula M. Mitchell, Thomas C. |
| spellingShingle |
Gandhapudi, Siva K. Chilton, Paula M. Mitchell, Thomas C. TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion |
| author_facet |
Gandhapudi, Siva K. Chilton, Paula M. Mitchell, Thomas C. |
| author_sort |
Gandhapudi, Siva K. |
| title |
TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion |
| title_short |
TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion |
| title_full |
TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion |
| title_fullStr |
TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion |
| title_full_unstemmed |
TRIF Is Required for TLR4 Mediated Adjuvant Effects on T Cell Clonal Expansion |
| title_sort |
trif is required for tlr4 mediated adjuvant effects on t cell clonal expansion |
| description |
Toll like receptor 4 (TLR4) is an important pattern recognition receptor with the ability to drive potent innate immune responses and also to modulate adaptive immune responses needed for long term protection. Activation of TLR4 by its ligands is mediated by engagement of the adapter proteins MyD88 (myeloid differentiation factor 88) and TRIF (Toll-interleukin 1 receptor domain-containing adapter inducing interferon-beta). Previously, we showed that TRIF, but not MyD88, plays an important role in allowing TLR4 agonists to adjuvant early T cell responses. In this study, we investigated the T cell priming events that are regulated specifically by the TRIF signaling branch of TLR4. We found that TRIF deficiency prevented the TLR4 agonist lipid A from enhancing T cell proliferation and survival in an adoptive transfer model of T cell priming. TRIF deficient DC showed defective maturation as evidenced by their failure to upregulate co-stimulatory molecules in response to lipid A stimulation. Importantly, TRIF alone caused CD86 and CD40 upregulation on splenic DC, but both TRIF and MyD88 were required for CD80 upregulation. The impairment of T cell adjuvant effects and defective DC maturation in TRIF lps/lps mice after TLR4 stimulation was mainly due to loss of type I IFN production, indicating that type I interferons are central to TLR4's adjuvant effects. These results are useful for the continued development of TLR4 based vaccine adjuvants that avoid inflammatory risks while retaining beneficial immune response. |
| publisher |
Public Library of Science |
| publishDate |
2013 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3574014/ |
| _version_ |
1611955422576508928 |