Summary of Europrise funded research studentship.
Natural killer (NK) cells play an important role in early immune defence against viral infections through their ability to kill host cells infected with viruses1. NK cells also have the ability to influence the generation of acquired immune responses2-4.
Our previous studies have shown that NK cell receptor expression changes and that their protective functions are compromised in peripheral blood and gastrointestinal tract of individuals infected with HIV-15-7.
Microbial products, including viral RNA and bacterial LPS stimulate innate immunity by acting initially on cells of the myeloid lineage, including dendritic cells. These cells in turn produce cytokines which activate innate natural killer cells8,9. Vaccine adjuvants also stimulate such innate immune pathways as these are in-turn required for the optimal co-stimulation of antigen-specific memory T-cells 10.
The first objective of this study is to establish and standardise assays for measurement of innate myeloid cell and NK cell activation by microbial products. These assays will subsequently be applied to adjuvants for potential HIV-1 vaccines to establish whether these can effectively stimulate innate immune components in both blood and gut mucosal tissue. Assays will be tested initially using samples from HIV-1 negative individuals as a model for the effects of adjuvants during prophylactic vaccination. Subsequently these tests will be applied to cells from HIV-1+ individuals to test whether adjuvant-driven myeloid cell and NK cell activating pathways can be recovered after anti-retroviral therapy and thus have potential during therapeutic vaccination.
The second objective is to characterise more fully the functional capacity of natural killer cells from gut mucosal tissue to establish their potential role as ‘helper’ NK cells for acquired immune responses.
A series of cellular and molecular techniques will be used to perform these investigations, including 6 colour flow cytometry, gene expression microarray analysis and cell separation and culture.
References
1.Biron, C.A. & Brossay, L. Curr Opin Immunol. 13, 458-64. (2001).
2.Mailliard, R.B. et al. J Exp Med. 202, 941-53. (2005).
3.Martin-Fontecha, A. et al. Nat Immunol. 5, 1260-5. (2004).
4.Hanna, J. & Mandelboim, O. Trends Immunol. 28, 201-6. (2007).
5.Mela, C.M. et al. AIDS. 19, 1761-9. (2005).
6.Goodier, M.R. et al. J Virol. 81, 430-3. (2007).
7.Mela, C.M., et al. AIDS 21, 2177-82 (2007).
8.Goodier, M.R. & Londei, M. J Immunol. 165, 139-47. (2000).
9.Nedvetzki, S. et al. Blood. 109, 3776-85. (2007).
10.Pulendran, B. & Ahmed, R. Cell. 124, 849-63. (2006).