Exploiting the potential of iNKT cells to improve vaccination

Alwethaynani, Maher (2022). Exploiting the potential of iNKT cells to improve vaccination. University of Birmingham. Ph.D.

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Abstract

Invariant (i)NKT cells are a subset of innate-like T cells that recognize glycolipids (such as α-galactosylceramide; α-GalCer) presented by the non-polymorphic MHC I-like molecule CD1d. The known specificity of iNKT cells combined with their capacity to secrete vast amounts of cytokine following activation makes them a candidate for manipulation to potentiate immune responses following vaccination. FliC is the fundamental building block of the flagella of Salmonella Typhimurium (STm) which has been shown to have potential as a vaccine due to it acting as its own adjuvant following recognition by TLR5. Indeed, FliC vaccination has been shown to generate both T and B cell responses to itself and confer a degree of protection from subsequent ST infection in mouse models.
We therefore sought to examine whether the coincident activation of iNKT cells would boost the immune response seen on FliC administration. To this end, mice were co-immunised with FliC and α-GalCer and the dynamics of the iNKT cell response, the conventional T cell response and the B cell/antibody response to FliC was compared to those in mice that received FliC immunisation only. we found that iNKT cell activation coincident with FliC vaccination boosts immunity following FliC vaccination by enhancing Ab production, increasing the number of Ab-secreting cells and boosting the GC reaction.
Strikingly, for optimal immunity following immunisation with FliC both TLR5 signalling and iNKT cells are required. However, the activation of iNKT cells could partially rescue Ab responses to FliC in the absence of TLR5 and the loss of NKT cells dramatically impacts the success of FliC immunisation. The use of an IFNγ-inducing glycolipid such as C-glycoside resulted in an even more robust adjuvant effect with a further increased the titre and longevity of serum IgG2C and IgA Ab over and above that seen with α-GalCer. Taken together the concomitant activation of iNKT cells can improve the efficacy of vaccines.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):