The complement system and invariant natural killer T (iNKT) cell responses
The recent discovery of intracellular complement activation, specifically anaphylatoxin generation and downstream autocrine receptor engagement in conventional α/β CD4+ T cells has provided new insights into mechanisms of T cell activation, polarisation, and homeostatic survival. Anaphylatoxin gener...
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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2021
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| _version_ | 1797109525172453376 |
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| author | Malik, N |
| author2 | Salio, M |
| author_facet | Salio, M Malik, N |
| author_sort | Malik, N |
| collection | OXFORD |
| description | The recent discovery of intracellular complement activation, specifically anaphylatoxin generation and downstream autocrine receptor engagement in conventional α/β CD4+ T cells has provided new insights into mechanisms of T cell activation, polarisation, and homeostatic survival. Anaphylatoxin generation by antigen-presenting cells (APCs) which leads to paracrine signalling via anaphylatoxin receptors on T cells has also been observed but is less extensively described. It is speculated that cell-derived complement may also influence the activity of non-conventional α/β T cells, specifically invariant Natural Killer T (iNKT) cells. The modulation of iNKT cell effector function by cell-derived complement may manifest in two ways, either through autocrine signalling events or via paracrine signalling by neighbouring APCs. Through a combination of molecular biology approaches, a thorough appraisal of iNKT complement expression profiles was performed. Specifically, iNKT cells were shown to up-regulate C3 and the anaphylatoxin receptors C3aR and C5aR1 on their cell surface upon activation with the canonical ligand α-GalCer. Moreover, iNKT cells may ‘recycle’ C3 from the extracellular space, to potentially regulate complement in their local microenvironment. As iNKT cells mature dendritic cells (DC) in a CD40L-dependent manner, subsequent work showed that engagement of the CD40-CD40L axis also influenced DC complement expression profiles. Specifically, the alternative pathway (AP) complement protein Factor B (FB) along with C3 were positively modulated by CD40 ligation. Moreover, pharmacological inhibition of FB by proprietary GSK inhibitors, specifically cell-permeable small molecules was shown to suppress DC effector function. Subsequent work which assessed cell-derived anaphylatoxin generation was undertaken to validate the specificity of pharmacological inhibition. In conclusion, potential crosstalk mechanisms between the CD40- CD40L axis and FB may underscore DC activation profiles. Modulation of DC effector function may in turn influence iNKT activation at the iNKT-APC interface. |
| first_indexed | 2024-03-07T07:42:56Z |
| format | Thesis |
| id | oxford-uuid:bb1be1bf-5257-447f-992d-aa757fcb5a51 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:42:56Z |
| publishDate | 2021 |
| record_format | dspace |
| spelling | oxford-uuid:bb1be1bf-5257-447f-992d-aa757fcb5a512023-05-04T08:38:16ZThe complement system and invariant natural killer T (iNKT) cell responsesThesishttp://purl.org/coar/resource_type/c_db06uuid:bb1be1bf-5257-447f-992d-aa757fcb5a51EnglishHyrax Deposit2021Malik, NSalio, MKolev, MDavis, SThe recent discovery of intracellular complement activation, specifically anaphylatoxin generation and downstream autocrine receptor engagement in conventional α/β CD4+ T cells has provided new insights into mechanisms of T cell activation, polarisation, and homeostatic survival. Anaphylatoxin generation by antigen-presenting cells (APCs) which leads to paracrine signalling via anaphylatoxin receptors on T cells has also been observed but is less extensively described. It is speculated that cell-derived complement may also influence the activity of non-conventional α/β T cells, specifically invariant Natural Killer T (iNKT) cells. The modulation of iNKT cell effector function by cell-derived complement may manifest in two ways, either through autocrine signalling events or via paracrine signalling by neighbouring APCs. Through a combination of molecular biology approaches, a thorough appraisal of iNKT complement expression profiles was performed. Specifically, iNKT cells were shown to up-regulate C3 and the anaphylatoxin receptors C3aR and C5aR1 on their cell surface upon activation with the canonical ligand α-GalCer. Moreover, iNKT cells may ‘recycle’ C3 from the extracellular space, to potentially regulate complement in their local microenvironment. As iNKT cells mature dendritic cells (DC) in a CD40L-dependent manner, subsequent work showed that engagement of the CD40-CD40L axis also influenced DC complement expression profiles. Specifically, the alternative pathway (AP) complement protein Factor B (FB) along with C3 were positively modulated by CD40 ligation. Moreover, pharmacological inhibition of FB by proprietary GSK inhibitors, specifically cell-permeable small molecules was shown to suppress DC effector function. Subsequent work which assessed cell-derived anaphylatoxin generation was undertaken to validate the specificity of pharmacological inhibition. In conclusion, potential crosstalk mechanisms between the CD40- CD40L axis and FB may underscore DC activation profiles. Modulation of DC effector function may in turn influence iNKT activation at the iNKT-APC interface. |
| spellingShingle | Malik, N The complement system and invariant natural killer T (iNKT) cell responses |
| title | The complement system and invariant natural killer T (iNKT) cell responses |
| title_full | The complement system and invariant natural killer T (iNKT) cell responses |
| title_fullStr | The complement system and invariant natural killer T (iNKT) cell responses |
| title_full_unstemmed | The complement system and invariant natural killer T (iNKT) cell responses |
| title_short | The complement system and invariant natural killer T (iNKT) cell responses |
| title_sort | complement system and invariant natural killer t inkt cell responses |
| work_keys_str_mv | AT malikn thecomplementsystemandinvariantnaturalkillertinktcellresponses AT malikn complementsystemandinvariantnaturalkillertinktcellresponses |