Review Article

Targeting TLR2 for Vaccine Development

Table 2

Immunomodulation by TLR2 ligands in mouse and human models.

TLR2 ligandaSpecies and cells/observationsbReference

Modulation of APC migration and antigen internalization
Recruitment of leukocytes
 Pam3CSK4Mouse/Recruitment of CD11b+ blood cells at injection site, mainly neutrophils[118]
Transient reduction of DC motility at inflammatory sites
 Pam3CSKMouse BM-DCs, spl. DCs/Podosome disassembly, increasing in cell spreading, switch from podosomes to focal contacts[120]
Increase in DC antigen internalization
 Pam3CSK4; Pam3CSKMouse BM-DCs, spl. DCs/Transiently increased pinocytosis [120, 129]
 Mouse anti-human TLR2 mAbHuman Mo-DCs/Internalization of an anti-TLR2 monoclonal antibody into endosomes [130]
 Pam3CSK4Mouse BM-DCs, D1 cells/TLR2-independent; clathrin- or caveolin dependent; covalent link-dependent[140]
Promotion of DC migration to regional lymph nodes
 Pam3CSK4Mouse BM-DCs, BM-Mf/inflammatory chemokine receptors, CCR7[125]

Antigen processing and presentation in the context of MHC class II
Enhanced presentation on MHC class II
 Pam3CSK4Mouse BM-DCs, spl. DCs/When antigen is coadministered with TLR2 ligand but not sequentially[129]
 MALP-2Mouse BM-DCs/When DCs are loaded with MHC class II Ova peptide in the presence of MALP-2[149]
Upregulation of costimulatory molecules and MHC class II
 rLipo-D1E3; OprI BLP; PGN, LTA; MALP-2Mouse BM-DCs[99, 147149]
 [Th]-K(P2CSS)-[B]D1 cells[142]
 Pam3CSK4; 19-kDa and Tp47 LPsHuman PBMC-DCs[145]
 [Th]-K(P2CSS)-[Tc]D1 cells[146]
 Pam3C Human  Mo-DCs[130]
 BPPcysMPEGMouse/ In vivo, in CD8α + and CD8α splenic DC subsets[150]
P. gingivalis LPSMouse/ In vivo, in CD8α + and CD8α splenic DC subsets[152]
 Pam3CSK4Mouse/ In vivo, in CD11c+CD11b+ and CD11c+CD11b splenic DC subsets[151]

CD4 + T cell polarization
Induction of Th2 responses
 Pam3CSK4Human Mo-DCs; Mouse/ERK1/2 signalling, stabilization of c-Fos, IL-12p70, of IL-10 [151, 153]
 FSL-1Mouse/Higher IgG1, lower IgG2a; IL-10 but not IL-12p70 by splenocytes; MAPK and c-Fos in splenocytes[154]
P. gingivalis LPSMouse/IL-13, IL-5, IL-10 but not IFN-γ by specific CD4+ T cells; no IL-12p70 by CD8α + DCs [152]
 Pam3CSK4Mouse/IL-13, IL-1β, GM-CSF, B7RP-1, but low IL-12, IFN-α, IL-18, IL-27 by BM-DCs. In vivo IgE and IgG1 but not IgG2a; IL-13 and IL-5 but not IFN-γ by specific CD4+ T cells after restimulation or i.n. challenge[155]
 PGN, Pam3C, and zymosanHuman Mo-DCs/No IL-12p70 while inducing IL-12p40. Related with the incapacity to induce type I IFN[156]
Induction of Th1 responses
 K(Pam)-[Th] versus K(Chol)-[Th]Mouse/Pam-LP induced higher IFN-γ and IL-2 and lower IL-4 by HSV1-specific CD4+ T cells and higher IgG2a/IgG1 ratio[117]
 OprI-COOHgp63 BLPMouse/IgG2a; Leishmaniosis protection correlated with IFN-γ production[143]
 [Th]-K(P2CSS)-[Tc]Human Mo-DCs/Production of IL-12p70 ≥ than that induced by LPS[157]
 Pam2CSK4 and Pam3CSK4Human/IFN-γ in CB-PBMCs co-cultured with allogeneic DCs[158]
 Pam3CSK4Mouse/IgG2a, IgG1 and no IgE after oral immunization with gliadin[159]
 Pam3C, 19-kDa, and Tp47 LPsHuman PBMCs and Mo/IFN-γ but not IL-4 in PBMCs; anti-IL-12 antibody T cell proliferation; IL-12p40 in Mo[160]
 PGN, Pam3C, Pam3CSK4Mouse splenocytes/IL-12p70 and IFN-γ (but less than LPS)[161]
 rlipo-E7mMouse/IL-12 in BM-DCs; Higher IFN-γ and lower IL-5 by restimulated splenocytes[162]
 19- and 38-kD BLPsHuman Mo; THP-1 cells/IL-12p40 in THP-1 cells; 19-kD lipoprotein IL-12p70 in Mo[87]
 19 kDa BLP; Tp47, OspA, and 19 kDa LPs; Pam3CSK4Human Mo-DCs and Mo/IL-12p40 and IL-10 in Mo; IL-12p40 and IL-12p70 in Mo-DCs (IL-12p70 higher for the lipoprotein than for the lipopeptides)[163]
 Pam3CSK4 and MALP-2Mouse Th1 cells/Direct stimulation IFN-γ, cellular survival and proliferation in the absence of TCR stimulation; not observed for ligands of other TLRs[164]
Induction of Th17 responses
 PGN, Pam3CSK4, MALP-2Human Mo-LC/MALP-2 and PGN IL-6, IL-1β, and IL-23 by Mo-LC; IL-17 by allogeneic CD4+ T cells cocultured with CD1+ Mo-LC stimulated with PGN or Pam3CSK4[165]
Induction of Th1/Treg differentiation and inhibition of Th2 responses
 OprI BLPMouse/airway eosinophilia, IL-4 and IL-13 after i.n. coadministration of OprI with Ova allergen[147]
 LP40Human PBMCs and T cells; Mouse in vivo  models./IL-10, IFN-γ and IL-12 by human PBMCs, both directly and on antigen restimulation; allergy in different models (Th2 cells, IgE, and eosinophilia)[166]
 Pam3CSK4Mouse/IL-12p35 and IL-10 in BM-DCs and oral myeloid DCs; treated DCs IFN-γ and IL-10 by naïve CD4+ T cells; Sublingual administration with antigen in Ova-sensitized mice airway hyperresponsiveness and Ova-specific IL-5 and IL-10 in cervical lymph nodes[167]
Regulatory role
 ZymosanHuman Mo-DCs and Mouse spl. DCs, in vitro; Mouse, in vivo/high IL-10, low IL-6 and IL-12p70 by DCs; In vivo: low costimulatory molecules on splenic DCs or proinflammatory cytokines, induction of specific T cells secreting IL-10 but little Th1 or Th2 cytokines, and unresponsiveness to challenge with the antigen plus adjuvant (IFA)[168]
 ZymosanMouse spl. DCs/Aldh1 and IL-10; leads to metabolize vitamin A and stimulate Treg cells[169]
 ZymosanMouse/T cells from treated mice showed reduced ability to induce diabetes in NOD-Scid mice[170]
 FSL-1Mouse/Treg cells in the draining lymph node and the growth of tumor. Anti-CD25 antibody abrogated the protumor activity of FSL-1[171]
 Pam2 lipopeptides Mouse/Treg cells in a TLR2- and IL-10- dependent manner[172]
Antiregulatory role
 Pam3CSK4Mouse/Direct activation of Tregs, with TCR and IL-2 stimulation, induced proliferation and temporary loss of suppressive properties, which are restored after removing the stimulus[173, 174]
 Pam3CSK4Mouse/suppressive function of Treg cells; tumor-specific CTL activity[175]
 Pam3CSK4Mouse/CD4+ effector T cells became resistant to Treg-mediated suppression[176]

Cross-presentation and CD8 + T cell cytotoxicity
Pam3CSK4-[Tc]Mouse/Induction of specific CTL responses higher than peptide admixed; In vitro cross-presentation of peptides in fusion, but not admixed, and independently of TLR2[140]
Th -K(P2CSS)- Tc HLA-A2kb transgenic Mouse; Human Mo-DCs/Induction of specific CTL responses. Lipopeptide-pulsed human DCs activated antigen-specific IFN-γ production by autologous CD8+ T cells[157]
Th -K(P2CSS)- Tc versus Pam2CSS- Th - Tc Mouse/Branched lipopeptide more potent in the primary response; both induced CTLs and conferred long-term protection against Ova-expressing tumor cells[177]
Th -K(Pam or Chol)- Tc Mouse/Induction of CTL responses by i.n. route and enhanced protection against influenza challenge[178]
Pam3CSS- Tc Mouse/Specific CTL activity induced in vivo against influenza virus[81]
Hda- Tc Mouse/Specific CTL activity induced in vivo against HIV-1 virus[179]
K(Pam)- Tc Human Mo-DCs/Lipopeptides but not the peptide were endocytosed; IFN-γ of matched specific CD8+ T-cells[180]
Pam3CSK4- Tc Mouse/Induced in vivo tetramer positive and IFN-γ producing CD8+ T cells[181]
MALP-2Mouse BM-DCs/immunoproteasome proteins LMP2, LMP7, and MECL; proteolytic activity[149]
(K(Pam))1,2,or 3- Th - Tc Mouse/specific antiviral CTL responses irrespective of the number of lipid moieties[182]
BPPcysMPEGMouse/specific CTL response in a TLR2 and CD4+ Th dependent manner, but independent of IFN-α. Direct link of the antigen to BPP CTL[150]
FSL-1Mouse/Immunization of FSL-1 and tumor-associated antigens specific CTLs[171]
rlipo-E7mMouse/CTL responses and therapeutic and prophylactic protection against tumor challenge[162]

Induction of NK cells activity
Stimulation of NK cell activity
 Pam2C lipopeptidesMouse/Variations in the activation capacity among lipopeptides with different peptide sequences [183]
 Pam2CSK4 versus MALP-2Mouse/MALP-2 much less effective in inducing NK cell activity[184]
Induction of ADCC by NK
 FSL-1Mouse/Coadministration with tumor associated antigens antitumor ADCC by NK cells[171]

Induction of antibody responses
Induction of antibody secreting cells (ASC) differentiation
 NatterinsMouse/Generation of long-lived ASCs[185]
 Pam2CSK4; Pam3CSK4Mouse/Together with CD40 signal, differentiation of B cells into ASCs[186]
Increasing of antibody responses
 Fusion lipoproteinsMouse[99, 143]
 Synthetic lipopeptidesMouse[117, 146, 154, 155]

Induction of mucosal responses
Immunization via mucosal surfaces
 ((Pam)K)3- Th - Tc Mouse/Intravaginally delivery HSV-2-specific memory CTLs locally and in the spleen. Significantly weaker response observed in TLR2−/− mice[187]
 MAP-Pam3CMouse/specific IgA in mucosal secretions and IgG in the serum after oral immunization. Intragastric delivery systemic T cell stimulation and specific CTL activity[188]
 LT-IIa-B5Mouse/i.n. immunization recruited DCs to the NALT, antigen uptake, CCR7 and migration to draining lymph node. TLR2-dependent of specific CD4+ T cell proliferation, salivary IgA, and serum IgG[124]
 Pam3CSK4Mouse/i.n. immunization enhanced serum antibody responses and protection against influenza[189]
Th]-K(P2CSS)- Tc Mouse/i.n. immunization induced CD8+ CTL responses in the lung and systemic after influenza challenge[146]
Mucosal imprinting of specific immunity
 Pam3CSK4Mouse/Pretreatment of extraintestinal DCs retinal dehydrogenases and confer the capacity to induce gut-homing lymphocytes[190]

rLipo-D1E3 and rlipo-E7m: Domain 1 of the Ag473 lipoprotein from Neisseria meningitidis fused to a sequence of dengue virus envelope protein (E3) or inactive E7 oncoprotein of human papillomavirus (E7m); OprI or OprI-COOHgp63 BLPs: outer membrane lipoprotein I from Pseudomonas aeruginosa, alone or fused with a truncated 32-kDa version, the major cell surface glycoprotein gp63 of Leishmania major; [Th]: CD4+ T cell epitope; [Tc]: CD8+ T cell epitope; [B]: B cell epitope; K: Lysine with a palmitic (Pam), diacylated (P2CSS), or cholesterol (Chol) moiety attached to -amino group; 19-kDa, Tp47, and OspA LP: synthetic tripalmitoyl lipopeptides based on the sequences of 19-kDa lipoprotein from Mycobacterium tuberculosis, 47-kDa lipoprotein from Treponema pallidum, and OspA lipoprotein from Borrelia burgdorferi; 19-kDa and 38-kD BLP: 19-kDa and 38-kD lipoproteins from Mycobacterium tuberculosis; LP40: synthetic lipopeptide CGP 40774; Hda: α-aminohexadecanoic acid; BPPcysMPEG: pegylated synthetic derivative of MALP-2; MAP: multiple antigen peptide; LT-IIa-B5: pentameric B subunit of type IIa enterotoxin of Escherichia coli.
: enhancement; : decrease; BM-DCs: bone marrow-derived DCs; spl. DCs: splenic DCs; Mo-DCs: monocyte-derived dendritic cells; Mo: monocytes; Mo-LC: monocyte-derived Langerhan-like cells; D1 cells: a line of immature DCs derived from spleen cells; PBMC-DCs: PBMC-derived DCs; CB-PBMCs: cord blood-derived PBMCs; THP-1 cells: human monocytic cell line; i.n.: intranasal.