Suppression of Th1 priming by TLR2 agonists during cutaneous immunization is mediated by recruited CCR2+ monocytes

Christopher T. Johndrow, Michael F. Goldberg, Alison J. Johnson, Tony W. Ng, Shajo Kunnath-Velayudhan, Gregoire Lauvau, Daniel H. Kaplan, Graeme H. Gossel, Ulrich D. Kadolsky, Andrew J. Yates, John Chan, William R. Jacobs, Steven A. Porcelli

Research output: Contribution to journalArticle

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Abstract

Effective subunit vaccines require the incorporation of adjuvants that stimulate cells of the innate immune system to generate protective adaptive immune responses. Pattern recognition receptor agonists are a growing class of potential adjuvants that can shape the character of the immune response to subunit vaccines by directing the polarization of CD4 T cell differentiation to various functional subsets. In the current study, we applied a high-throughput in vitro screen to assess murine CD4 T cell polarization by a panel of pattern recognition receptor agonists. This identified lipopeptides with TLR2 agonist activity as exceptional Th1-polarizing adjuvants. In vivo, we demonstrated that i.v. administration of TLR2 agonists with Ag in mice replicated the findings from in vitro screening by promoting strong Th1 polarization. In contrast, TLR2 agonists inhibited priming of Th1 responses when administered cutaneously in mice. This route-specific suppression was associated with infiltrating CCR2+ cells in the skin-draining lymph nodes and was not uniquely dependent on any of the well characterized subsets of dendritic cells known to reside in the skin. We further demonstrated that priming of CD4 T cells to generate Th1 effectors following immunization with the Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain, a lipoprotein-rich bacterium recognized by TLR2, was dependent on the immunization route, with significantly greater Th1 responses with i.v. compared with intradermal administration of BCG. A more complete understanding of route-dependent TLR2 responses may be critical for informed design of novel subunit vaccines and for improvement of BCG and other vaccines based on live-attenuated organisms. The Journ Al of Immunology, 2018, 201: 3604-3616.

Original languageEnglish (US)
Pages (from-to)3604-3616
Number of pages13
JournalJournal of Immunology
Volume201
Issue number12
DOIs
StatePublished - Dec 15 2018

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Subunit Vaccines
Bacillus
Pattern Recognition Receptors
Monocytes
Immunization
T-Lymphocytes
Skin
Lipopeptides
Adaptive Immunity
Mycobacterium bovis
Allergy and Immunology
Dendritic Cells
Lipoproteins
Cell Differentiation
Immune System
Vaccines
Lymph Nodes
Bacteria
In Vitro Techniques

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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Suppression of Th1 priming by TLR2 agonists during cutaneous immunization is mediated by recruited CCR2+ monocytes. / Johndrow, Christopher T.; Goldberg, Michael F.; Johnson, Alison J.; Ng, Tony W.; Kunnath-Velayudhan, Shajo; Lauvau, Gregoire; Kaplan, Daniel H.; Gossel, Graeme H.; Kadolsky, Ulrich D.; Yates, Andrew J.; Chan, John; Jacobs, William R.; Porcelli, Steven A.

In: Journal of Immunology, Vol. 201, No. 12, 15.12.2018, p. 3604-3616.

Research output: Contribution to journalArticle

Johndrow, CT, Goldberg, MF, Johnson, AJ, Ng, TW, Kunnath-Velayudhan, S, Lauvau, G, Kaplan, DH, Gossel, GH, Kadolsky, UD, Yates, AJ, Chan, J, Jacobs, WR & Porcelli, SA 2018, 'Suppression of Th1 priming by TLR2 agonists during cutaneous immunization is mediated by recruited CCR2+ monocytes', Journal of Immunology, vol. 201, no. 12, pp. 3604-3616. https://doi.org/10.4049/jimmunol.1801185
Johndrow, Christopher T. ; Goldberg, Michael F. ; Johnson, Alison J. ; Ng, Tony W. ; Kunnath-Velayudhan, Shajo ; Lauvau, Gregoire ; Kaplan, Daniel H. ; Gossel, Graeme H. ; Kadolsky, Ulrich D. ; Yates, Andrew J. ; Chan, John ; Jacobs, William R. ; Porcelli, Steven A. / Suppression of Th1 priming by TLR2 agonists during cutaneous immunization is mediated by recruited CCR2+ monocytes. In: Journal of Immunology. 2018 ; Vol. 201, No. 12. pp. 3604-3616.
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AU - Goldberg, Michael F.

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AU - Ng, Tony W.

AU - Kunnath-Velayudhan, Shajo

AU - Lauvau, Gregoire

AU - Kaplan, Daniel H.

AU - Gossel, Graeme H.

AU - Kadolsky, Ulrich D.

AU - Yates, Andrew J.

AU - Chan, John

AU - Jacobs, William R.

AU - Porcelli, Steven A.

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N2 - Effective subunit vaccines require the incorporation of adjuvants that stimulate cells of the innate immune system to generate protective adaptive immune responses. Pattern recognition receptor agonists are a growing class of potential adjuvants that can shape the character of the immune response to subunit vaccines by directing the polarization of CD4 T cell differentiation to various functional subsets. In the current study, we applied a high-throughput in vitro screen to assess murine CD4 T cell polarization by a panel of pattern recognition receptor agonists. This identified lipopeptides with TLR2 agonist activity as exceptional Th1-polarizing adjuvants. In vivo, we demonstrated that i.v. administration of TLR2 agonists with Ag in mice replicated the findings from in vitro screening by promoting strong Th1 polarization. In contrast, TLR2 agonists inhibited priming of Th1 responses when administered cutaneously in mice. This route-specific suppression was associated with infiltrating CCR2+ cells in the skin-draining lymph nodes and was not uniquely dependent on any of the well characterized subsets of dendritic cells known to reside in the skin. We further demonstrated that priming of CD4 T cells to generate Th1 effectors following immunization with the Mycobacterium bovis bacillus Calmette-Guérin (BCG) strain, a lipoprotein-rich bacterium recognized by TLR2, was dependent on the immunization route, with significantly greater Th1 responses with i.v. compared with intradermal administration of BCG. A more complete understanding of route-dependent TLR2 responses may be critical for informed design of novel subunit vaccines and for improvement of BCG and other vaccines based on live-attenuated organisms. The Journ Al of Immunology, 2018, 201: 3604-3616.

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