TOLLIP Optimizes Dendritic Cell Maturation to Lipopolysaccharide and Mycobacterium tuberculosis .
Sambasivan VenkatasubramanianRobyn PryorCourtney R PlumleeSarah B CohenJason D SimmonsAlexander J WarrAndrew D GrausteinAparajita SahaThomas R HawnKevin B UrdahlJaveed A ShahPublished in: Journal of immunology (Baltimore, Md. : 1950) (2022)
TOLLIP is a central regulator of multiple innate immune signaling pathways, including TLR2, TLR4, IL-1R, and STING. Human TOLLIP deficiency, regulated by single-nucleotide polymorphism rs5743854, is associated with increased tuberculosis risk and diminished frequency of bacillus Calmette-Guérin vaccine-specific CD4 + T cells in infants. How TOLLIP influences adaptive immune responses remains poorly understood. To understand the mechanistic relationship between TOLLIP and adaptive immune responses, we used human genetic and murine models to evaluate the role of TOLLIP in dendritic cell (DC) function. In healthy volunteers, TOLLIP single-nucleotide polymorphism rs5743854 G allele was associated with decreased TOLLIP mRNA and protein expression in DCs, along with LPS-induced IL-12 secretion in peripheral blood DCs. As in human cells, LPS-stimulated Tollip -/- bone marrow-derived murine DCs secreted less IL-12 and expressed less CD40. Tollip was required in lung and lymph node-resident DCs for optimal induction of MHC class II and CD40 expression during the first 28 d of Mycobacterium tuberculosis infection in mixed bone marrow chimeric mice. Tollip -/- mice developed fewer M. tuberculosis -specific CD4 + T cells after 28 d of infection and diminished responses to bacillus Calmette-Guérin vaccination. Furthermore, Tollip -/- DCs were unable to optimally induce T cell proliferation. Taken together, these data support a model where TOLLIP-deficient DCs undergo suboptimal maturation after M. tuberculosis infection, impairing T cell activation and contributing to tuberculosis susceptibility.
Keyphrases
- mycobacterium tuberculosis
- dendritic cells
- immune response
- inflammatory response
- lps induced
- pulmonary tuberculosis
- lymph node
- toll like receptor
- bone marrow
- cell proliferation
- peripheral blood
- hiv aids
- emergency department
- metabolic syndrome
- regulatory t cells
- machine learning
- squamous cell carcinoma
- gene expression
- dna methylation
- poor prognosis
- early stage
- type diabetes
- cell cycle
- genome wide
- patient safety
- signaling pathway
- big data
- innate immune
- neoadjuvant chemotherapy
- high fat diet induced
- transcription factor
- nuclear factor
- quality improvement
- oxidative stress
- wild type
- sentinel lymph node
- pluripotent stem cells