Use this URL to cite or link to this record in EThOS:
Title: Understanding the molecular basis for T-cell induced pro and anti-inflammatory functions of monocytes
Author: Dickinson, Abigail Kate
ISNI:       0000 0004 7970 0455
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2019
Availability of Full Text:
Access from EThOS:
Full text unavailable from EThOS. Restricted access.
Access from Institution:
Monocytes and macrophages are innate immune cells that play a role in the initiation, propagation and resolution of inflammation. In addition, the balance between effector (Teff) and regulatory (Treg) T-cells promotes appropriate responses to immune challenge. Both Teff and Treg can interact with cells in the innate immune system to promote phenotypic and functional differentiation. Upon stimulation, effector T-cells release cytokines which can polarise macrophages phenotype. Regulatory T-cells are immunosuppressive and have been shown to inhibit DC maturation, cytokine release and surface marker expression. Our lab previously showed that Tregs can induce an "alternatively activated" phenotype in monocytes. This study aimed to identify further phenotypic, functional and molecular consequences of Teff and Treg monocyte modulation, in order to better understand the interplay of these cells in homeostasis and disease. Upon co-culture with Teffs, monocytes released increased LPS-induced pro-inflammatory cytokines and upregulated the expression of activation markers. Upon co-culture with Tregs, monocytes showed a suppression of LPS-induced pro-inflammatory cytokine responses and upregulated cell-surface markers associated with immune resolution. Cytokine responses to other TLR-ligands were varied. To better understand the molecular consequences of T-cell co-culture, a novel dataset was generated. RNA-sequencing was performed on re-sorted monocytes, modulated by either Teffs or Tregs. RNA-sequencing (n=11) revealed 1,521 significantly differentially expressed genes (DEG) in Teff-modulated monocytes and 1,066 DEG in Treg-modulated monocytes, vs. monocytes cultured alone. 381 of these genes were differentially expressed in both conditions. Evaluation of +Teff vs.+Treg-monocyte gene signatures exposed differential regulation of genes associated with immune cell function. The +Teff-monocyte gene signature was enriched for pro-inflammatory genes, and those related to apoptosis whereas an opposing gene signature was seen in the +Treg-monocyte condition. Furthermore, IPA revealed that genes associated with "phagocytosis" and "engulfment of cells" were upregulated in +Treg-monocytes and downregulated in +Teff-monocytes compared to monocytes alone. Assessment of efferocytic receptor expression revealed decreased expression in +Teff modulated monocytes and increased expression in +Treg modulated monocytes. Monocytes co-cultured with +Teff or CD4+ T-cells showed significantly reduced efferocytic ability. Similarly, oxLDL uptake was reduced in +Teff-modulated monocytes, in conjunction with a reduction in the oxLDL receptor CD36. Taken together, these data imply that +Teff modulated monocytes are highly activated cells, with a reduced capacity for engulfment of bacteria, apoptotic cells and oxLDL. Conversely, these data imply that Treg do not merely supress monocyte function, but specifically re-program these cells to a distinct phenotype.
Supervisor: Taams, Leonie Suzanne ; Guermonprez, Pierre ; Geissmann, Frederic Henri Lucien Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available