Activated Human Neonatal CD8+ T Cells Are Subject to Immunomodulation by Direct TLR2 or TLR5 Stimulation

Abstract

In conditions of optimal priming, the neonate possess competency to mount quantitatively adult-like responses. Vaccine formulations containing sufficiently potent adjuvants may overcome the neonates’ natural tendency for immunosuppression and provoke a similarly robust immune response. TLR expression on T cells represents the possibility of directly enhancing T cell immunity. We examined the ex vivo responsiveness of highly purified human cord blood-derived CD8+ T cells to direct TLR ligation by a repertoire of TLR agonists. In concert with TCR stimulation, only Pam3Cys (palmitoyl-3-Cys-Ser-(Lys)4) and flagellin monomers significantly enhanced proliferation, CD25+ expression, IL-2, IFN-γ, TNF-α, and intracellular granzyme B expression. TLR2 and TLR5 mRNA was detected in the CD8+ T cells. Blocking studies confirmed that the increase in IFN-γ production was by the direct triggering of surface TLR2 or TLR5. The simultaneous exposure of CD8+ T cells to both TLR agonists had an additive effect on IFN-γ production. These data suggest that a combination of the two TLR ligands would be a potent T cell adjuvant. This may represent a new approach to TLR agonist-based adjuvant design for future human neonatal vaccination strategies requiring a CD8+ component.

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

“…Our initial rationale for choosing flagellin hinged on its capacity to promote a T cell response, given the known expression of TLR5 on primate T cells (67), with the hypothesis that this would support the antibody response. Further, there are data supporting the ability of flagellin to enhance the activation of T cells isolated from infants (40). Specifically, cord blood-derived CD8 ϩ T cells exhibited increased levels of proliferation and IFN-␥ production when stimulated in the presence of flagellin (40).…”

“…Further, there are data supporting the ability of flagellin to enhance the activation of T cells isolated from infants (40). Specifically, cord blood-derived CD8 ϩ T cells exhibited increased levels of proliferation and IFN-␥ production when stimulated in the presence of flagellin (40). While it has not yet been reported, if flagellin engagement by neonatal CD4 ϩ T cells has a similar effect, which seems likely, given the expression of TLR5 on CD4 ϩ T cells (68), then we would predict that flagellin could support the generation of a Th response that promotes antibody production.…”

“…First, it can directly activate human dendritic cells (39). Second, flagellin provides a direct stimulatory signal to human T cells, promoting increases in both proliferation and cytokine production (40). In mouse models, it was reported to augment recruitment of T and B cells to secondary lymphoid sites (41).…”

Activation of Toll-Like Receptor 2 Prevents Suppression of T-Cell Interferon γ Production by Modulating p38/Extracellular Signal-Regulated Kinase Pathways following Alcohol and Burn Injury

“…Yet, when cultured with anti-CD3 with/without Pam3Cys-SK (TLR2 ligand) or LPS (TLR4 ligand), only Pam3Cys-SK increased T-cell proliferation and IFN-γ production (20). Similarly, recent studies have indicated that CD3/CD28-activated CD8+ T cells are functionally responsive to direct stimulation by TLR2 ligand Pam3CYs (38). In the absence of specific antigen, TLR2 acts as a costimulatory receptor on CD8+ T cells to directly control memory CD8+ T-cell proliferation and IFN-γ production (39).…”

Mycobacterium tuberculosis Lipoproteins Directly Regulate Human Memory CD4 + T Cell Activation via Toll-Like Receptors 1 and 2

“…Recent studies demonstrate that TLRs are also expressed on T lymphocytes, including CD4 ϩ , CD8 ϩ , and Foxp3 ϩ regulatory T cells. TLR2, TLR5, and TLR7-TLR8 (TLR7/8) can provide a second signal for activation of T cells upon TCR engagement (3,10,25,27,30,33). M. tuberculosis expresses several TLR ligands, including the cell membrane-associated lipoproteins LpqH (Rv3763), LprG (Rv1411c), and LprA (Rv1270c); cell wall glycolipids (TLR2); and mycobacterial DNA containing CpG motifs (TLR9) (18,19,28,37,41).…”