A study of invariant NKT cell biology in health and disease

Invariant NKT cells (iNKT cells) have been increasingly recognised as an important cell type in regulating certain immune responses. Advances in the understanding of iNKT biology have provided opportunities for manipulating their functions for combating malignant, infective and autoimmune diseases. During the tenure of my thesis I have explored aspects of iNKT function in healthy individuals, assessed the activity of novel iNKT compounds in an ex vivo human system and evaluated this important conserved T cell subset in a human disease setting. iNKT cells were initially evaluated in healthy individuals to explore whether there were differences in their function and development that co-associated with an enumeration that extended over a three log range. We performed phenotypic and functional assessments of ex vivo, polyclonal iNKT cells in 47 healthy donors. We established that those individuals with low numbers of iNKT cells (<200/105 T cells) displayed a different iNKT phenotype and functional profile to those with a high numbers of iNKT cells (>500/105 T cells). Following the establishment of a robust screening platform for human iNKT responses a series of 14 novel iNKT cell ligands were designed and analysed for functional distinctiveness from the prototypic !-GC ligand. We identified ligands that had been modified in the acyl and sphingosine chains, which both dissociated iNKT proliferation from cytokine production and skewed effector responses in a Th1, Th2 or Th17 direction. We similarly identified novel compounds that were able to reduce iNKT anergy after initial activation. Finally we showed that these functional differences were modified by CD1d affinity and the nature of the antigen presenting cell, co existent cytokines and donor phenotype. Lastly, we applied our iNKT investigative tools to a clinical disease where the link between iNKT cells and B cell help for antibody production was a possibility. We showed that in the commonest antibody deficiency syndrome, common variable immunodeficiency, iNKT were absent or functionally impaired in the majority of cases and that their number was correlated with presence of memory B cells

Name dc:type.qualificationname

Ph.D.

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Southampton

Year dc:date.issued

2010

Author dc:creator

• Gao, Yifang

Advisor dc:contributor.advisor

• Williams, Anthony P.