Theoretical immunology
Principal Investigator
CD8+ T cell epitope prediction software
Postdoctoral Position Available
We will shortly be advertising a 3 year MRC-funded postdoctoral position in Mathematical Immunology. Start date is flexible but will be around Oct 2012.
Group members
Becca Asquith (PI)
Nafisa-Katrin Seich al Basatena
Sukhdeep Singh
Ulrich Kadolsky
Aidan Macnamrra
Research Interests
What constitutes an effective CD8+ T cell response? And does CD8+ T cell efficacy determine human health? We aim to answer these questions with the long term goal of a deterministic, predictive model to guide the manipulation of adaptive immunity to alleviate human disease. We are working to develop, validate and apply the approaches necessary to achieve this goal. There are 3 key areas to be tackled: we need to quantify CD8+ T cell efficacy, identify the determinants of CD8+ T cell efficacy and assess the in vivo relevance of CD8+ T cells.
(i) Quantifying CD8+ T cell efficiency
Our work to quantify CD8+ T cell efficacy includes the development of novel techniques to measure the strength of the CD8+ T cell response in HIV-1, SIV-1, and HTLV-I infections1-3. This provided the first quantitative insight into the strength of the human HIV-specific CD8+ T cell response in vivo. We showed that the majority of infected cell death cannot be attributed to CD8+ T cells. We also demonstrated that CD8+ T cell killing is more efficient in SIV-infected macaques than HIV-infected humans. This indicates that the macaque model may be an over-optimistic model of CD8+ T cell control with important consequences for the interpretation of HIV vaccine studies which are routinely conducted in macaques. These techniques have been widely used by ourselves and others and have been adopted by the National Centre for Human Retrovirology as clinical trial endpoints.
(ii) What determines the efficiency of the CD8+ T cell response?
To investigate the determinants of CD8+ T cell efficiency we developed an innovative approach that integrates improved methods for epitope prediction4 with experimental data and cohort analysis. This resource is available online. Application of this method has enabled us to identify the constituents of a protective CD8+ T cell response to HTLV-I infection5. Extending this approach to HCV led us to find an unanticipated, enhancing role for an “innate receptor” (KIR2DL2) in adaptive immunity6, 7.
(iii) Investigating the in vivo relevance of CD8+ T cells
One of the most contentious questions in the field is “how important is the CD8+ T cell response”; i.e. does it really matter to an individual if their CD8+ T cell response is functioning efficiently or not. Here we have quantified T cell turnover in vivo in HTLV-I infected patients8; estimated the impact on HIV viral load of viral escape from the CTL response9; quantified the relative importance of CD8+ T cells, B cells and NK cells in determining the course of acute viremia in primary SIV infection10 and investigated the relative importance of lytic and non-lytic CD8+ effector mechanisms11.
We also work extensively on models to assess the relationship between lymphocyte dynamics and disease, such as the disregulation of B cell kinetics in patients with chronic lymphocytic leukaemia8, 12-15. This included development and application of models of deuterated glucose, BrdU and CFSE labelling.
Selected Recent Publications
1. Asquith, Edwards, Lipsitch, and McLean, Inefficient CTL-mediated killing of HIV-1-infected cells in vivo. PLoS Biology, 2006. 4(4 E90): p. 0583-0592.
2. Asquith and McLean, In vivo CD8+ T Cell Killing of Immunodeficiency Virus-Infected Cells in Humans and Macaques. Proceedings of the National Academy of Sciences of the United States of America, 2007. 104(15)(15): p. 6365-6370.
3. Asquith, Mosley, Barfield, Marshall, Heaps, Goon, Hanon, Tanaka, Taylor, and Bangham, A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load. J Gen Virol, 2005. 86(Pt 5): p. 1515-23.
4. MacNamara, Kadolsky, Bangham, and Asquith, T-cell epitope prediction: rescaling can mask biological variation between MHC molecules. PLoS Comput Biol, 2009. 5(3): p. e1000327.
5. Macnamara, Rowan, Hilburn, Kadolsky, Fujiwara, Suemori, Yasukawa, Taylor, Bangham, and Asquith, HLA class I binding of HBZ determines outcome in HTLV-1 infection. PLoS Path, 2010. 6(9): p. e1001117.
6. Seich Al Basatena, Macnamara, Vine, Thio, Astemborski, Usuku, Osame, Kirk, Donfield, Goedert, Bangham, Carrington, Khakoo, and Asquith, KIR2DL2 Enhances Protective and Detrimental HLA Class I-Mediated Immunity in Chronic Viral Infection. PLoS Pathogens, 2011. 7(10): p. e1002270.
7. Elemans, Seich Al Basatena, and Asquith, The Efficiency of the Human CD8+ T Cell Response: How Should we Quantify it, What Determines it and Does it Matter? PLoS Comput Biol (in press), 2011.
8. Asquith, Zhang, Mosley, de Lara, Wallace, Worth, Kaftantzi, Meekings, Griffin, Tanaka, Tough, Beverley, Taylor, Macallan, and Bangham, In Vivo T Lymphocyte Dynamics in Humans: The Impact of Human T Lymphotropic Virus I Infection. Proc Natl Acad Sci U S A, 2007. 104(19): p. 8035-8040.
9. Kadolsky and Asquith, Quantifying the impact of human immunodeficiency virus-1 escape from cytotoxic T-lymphocytes. PLoS Comput Biol, 2010. 6(11): p. e1000981.
10. Elemans, Thiebaut, Kaur, and Asquith, Quantification of the relative importance of CTL, B cell, NK cell, and target cell limitation in the control of primary SIV-infection. PLoS Comput Biol, 2011. 7(3): p. e1001103.
11. Elemans, Nafisa-Katrin Seich al Basatena, Klatt, Gkekas, Silvestri, and Asquith, Why don’t CD8+ T cells reduce the lifespan of SIV-infected cells in vivo? PLoS Comput Biol 2011. 7(9): p. e1002200.
12. Asquith, Debacq, Florins, Gillet, Sanchez-Alcaraz, Mosley, and Willems, Quantifying lymphocyte kinetics in vivo using carboxyfluorescein diacetate succinimidyl ester (CFSE). Proc Biol Sci, 2006. 273(1590): p. 1165-71.
13. Macallan, Wallace, Zhang, Ghattas, Asquith, de Lara, Worth, Panayiotakopoulos, Griffin, Tough, and Beverley, B-cell kinetics in humans: rapid turnover of peripheral blood memory cells. Blood, 2005. 105(9): p. 3633-40.
14. Macallan, Asquith, Zhang, de Lara, Ghattas, Defoiche, and Beverley, Measurement of proliferation and disappearance of rapid turnover cell populations in human studies using deuterium-labeled glucose. Nat Protoc, 2009. 4(9): p. 1313-27.
15. Lezin, Gillet, Olindo, Signate, Grandvaux, Verlaeten, Belrose, de Carvalho Bittencourt, Hiscott, Asquith, Burny, Smadja, Cesaire, and Willems, Histone deacetylase mediated transcriptional activation reduces proviral loads in HTLV-1 associated myelopathy/tropical spastic paraparesis patients. Blood, 2007. 110(10): p. 3722-8.
If you would like copies of these or any of our other papers please feel free to email me (b.asquith@imperial.ac.uk).
