The activation status of human macrophages presenting antigen determines the efficiency of Th17 responses

Abstract

Macrophages are antigen presenting cells that can adopt different activation states as directed by microenvironmental stimuli. It is well-recognised how CD4(+) T helper (Th) signals drive macrophage activation, but the ability of differentially activated human macrophages to stimulate the major types of CD4(+) T helper (Th) response by presenting antigen have not been well defined. Previous studies have focussed on murine cells, undifferentiated human monocytes, or macrophage products, and have been limited to non-physiological mitogenic Th responses. The aim was therefore to compare the Th cell polarising abilities of different human macrophage subsets when presenting specific antigen. We demonstrate for the first time that the way macrophages are activated, while naturally presenting antigen, has profound effects on downstream adaptive immune responses. In autologous co-cultures, LPS-activation was the most potent stimulus for antigen-loaded macrophages to drive Th17 polarisation from both unfractionated CD4(+) T-cells and the CD45RO(+) memory population, while IFNγ/LPS activated macrophages preferentially induced a Th1 phenotype. By contrast, IL-4-activated macrophages were ineffective in inducing responses by either Th subset. Although antigen-loaded dendritic cells were superior to macrophages in driving Th1 responses, the Th17 polarising capacity of the two antigen-presenting cell types was equivalent, and was strongly dependent on IL-1β secretion. Taken together, these results clearly demonstrate for the first time how differentially activated human macrophages present antigen to bias specific, rather than mitogen-driven, Th responses and lead us to propose that they impact adaptive immunity in vivo, particularly in determining Th17 polarisation within inflamed tissues.

Activation of Myeloid TLR4 Mediates T Lymphocyte Polarization after Traumatic Brain Injury

“…In keeping with a pro-inflammatory myeloid shift, we observed a TLR4-dependent increase in T H 1 and T H 17 polarization with a concomitant reduction in T REG in both blood and brain for 3 weeks after TBI. Notably, the exogenous TLR4 agonist, lipopolysaccharide (LPS), was the most potent stimulus for antigen-loaded macrophages to drive T H 17 polarization in human autologous co-cultures (50). Although T-lymphocytes do not routinely cross the blood-brain barrier (BBB) (51), intraperitoneal LPS administration increased the differentiation and brain influx of T H 17 cells after neonatal hypoxia-ischemia (52).…”

“…Adoptive transfer of myelin-specific T H 17 cells increased basal hippocampal neurogenesis via actions in peripheral lymphoid tissues whereas the same myelin-reactive T H 17 cells impaired endogenous remyelination in cuprizone-fed mice (69, 70). An explanation for these paradoxical effects is unclear, but the activation status of human antigen-presenting macrophages may dictate the efficiency of T H 17 responses (50). Adoptive transfer of T H 17 cells derived after TGF-β and IL-6 treatment are not detrimental whereas T H 17 cells generated by treatment with TGFβ, IL-6, and IL-23 induced symptoms of EAE (71).…”

Transient blocking of NK cell function with small molecule inhibitors for helper dependant adenoviral vector-mediated gene delivery

“…5 effective inhibition of NK cell response at its peak will also inhibit HD-Ad capsid mediated adaptive immune response. Cutting the arm leading to adaptive immune response will help in the redelivery of HD-Ad vectors for gene therapy as dampened antigen presentation happens with suppressed macrophage and NK cell response [56, 57].

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Interactions of hyperhomocysteinemia and T cell immunity in causation of hypertension

“…Though the direct evidence for oxidative damage in DCs by HHcy is yet to be produced, given its role in induction of oxidative stress in macrophages, T cells, and endothelial cells (Chernyavskiy et al 2016; Winchester et al 2015; Zhang et al 2002), such a role for HHcy in the context of hypertension is a possibility. It was recently noted that macrophage polarization can also influence the T cell polarization (Arnold et al 2015). For instance, M1 polarization with lipopolysaccharide (LPS) in the presence or absence of IFNγ can substantially determine the T helper cell polarization to Th1 or Th17, respectively (Arnold et al 2015).…”

“…It was recently noted that macrophage polarization can also influence the T cell polarization (Arnold et al 2015). For instance, M1 polarization with lipopolysaccharide (LPS) in the presence or absence of IFNγ can substantially determine the T helper cell polarization to Th1 or Th17, respectively (Arnold et al 2015). Such differential T helper cell polarization assumes utmost significance in hypertension development with the studies that implicated IL-17 producing Th17 cells in hypertension development (Harrison 2014; Madhur et al 2010).…”