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Title: Natural Killer cell function after vaccination in an African (Gambian) population
Author: Darboe, A.
ISNI:       0000 0004 6351 0550
Awarding Body: London School of Hygiene & Tropical Medicine
Current Institution: London School of Hygiene and Tropical Medicine (University of London)
Date of Award: 2017
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Emerging evidence suggests that NK cells could be important in the early effector response induced by vaccination, supported by vaccine antigen-specific CD4 IL-2 production and antigen-antibody immune complexes. 'Memory-like' NK cells, with heightened responsiveness can be also generated by pre-activation with cytokines. I found that NK cell differentiation is accelerated in Africans in The Gambia compared to age-matched UK residents and that this is linked to reduced functional NK cell responses to cytokines. This effect may also relate to a high burden of human cytomegalovirus (HCMV) infection in this population, with all Gambian study subjects infected by 3 years of age. There is also significant variation in lymphoid and myeloid cell populations with increasing age. Additionally, I found that a deletion of the NKG2C gene, a receptor important for recognition of HCMV infected cells, results in delayed NK cell differentiation. Furthermore, the allele frequency of the NKG2C gene deletion is higher in The Gambia compared to other countries studied to date. The frequency of the deletion allele did not change with age. I went on to investigate the impact of this advanced differentiation phenotype on NK cell responses in two vaccination studies: Gambian subjects of all ages made negligible NK cell CD107a, CD25, and IFN-γ responses to influenza or DTPiP vaccine antigens. No enhancement of these responses was observed after vaccination. However, vaccination resulted in intrinsic changes to NK cells with enhancement of NK cell IFN-γ responsiveness to exogenous cytokines. The main source of IFN-γ was derived from a population of CD56dimNKG2C+CD57- NK cells. These less differentiated cells may retain some capacity to control HCMV infection, and at the same time represent a possible target for generation of 'memory-like' NK cells in vivo in vaccine induced NK cell responses.
Supervisor: Riley, E. M. Sponsor: Medical Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral