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Toll-like receptor 4 and its direct impact on human CD4 T cells
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Toll-like receptors are mainly expressed on innate immune cells and play an important role in immune responses against pathogens by transducing signals in response to microbial products. TLR4 is well known for recognizing Lipopolysaccharide (LPS), and it has been also detected on activated human CD4 T cells at the mRNA level. However, TLR4 signaling specificities and their contribution for T lymphocyte functions remain unknown. We hypothesized that in addition to cytokines, other tissue microenvironment factors, such as the presence of LPS-bearing commensal and pathogenic bacteria can have an impact on human T cell phenotype. We showed for the first time that TLR4 is expressed in human CD4 T cells, both at the plasma membrane and in endosomal compartments. We found that direct recognition of LPS by activated CD4 T cells promotes their survival. Our results show that TLR4 engagement ensues two distinct signaling pathways driving distinct functional outcomes. At the plasma membrane, TLR4 drives pAKTS473 and p38 MAPKY182 activation, which might offer a mechanistic explanation for increased T cell survival. In addition, the plasma membrane is the site for TLR4 and TCR signaling cross-talk manifested by improved PKCθS676 phosphorylation. Surprisingly, once located to the endocytic compartment, TLR4 intersects TCR signaling by increasing the phosphorylation of a residue that has been described to be under the exclusive control of TCR engagement, p38 MAPKY323. By increasing the activation of p38 MAPKY323, TLR4 might impinge directly on CD4 T cell differentiation, due to the known role of this pathway in directing cytokine production. In this work we demonstrate how TLR4 signaling impinge on CD4 T cell functions namely manipulating cytokine production and the immune response. Our work might contribute to explain how immune plasticity is regulated by the tissue microenvironment, and how it might counteract chronic inflammations, an emerging field in immunology with elevated translational potential.
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Toll-like receptor 4 Human CD4 T cells Helper T cell plasticity Helper T cell counter-regulation Tissue protection novel therapeutic targets