University of Cambridge > Talks.cam > Immunology in Pathology > What constitutes a protective HLA class I molecule, and why doesn't it always work?

What constitutes a protective HLA class I molecule, and why doesn't it always work?

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Host: Peter Goon, pg336@cam.ac.uk

Abstract:

Two individuals, infected with an identical pathogen can have very different clinical outcomes. One determining factor is HLA class I genotype: different HLA class I alleles have been associated with significant protective or detrimental effects. However, the protective and detrimental HLA molecules do not always “work”; i.e. we see incomplete penetrance of the protective and detrimental traits. I will present our work to understand what makes an HLA class I molecule protective or detrimental and why these effects are not seen consistently for all cohorts.

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 KIR2DL2 in adaptive immunity.

(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 patients6, estimated the impact on HIV viral load of viral escape from the CTL response7 and quantified the relative importance of CD8 + T cells, B cells and NK cells in determining the course of acute viremia in primary SIV infection. 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 leukaemia6, 8-11. This included development and application of models of deuterated glucose, BrdU and CFSE labelling.

This talk is part of the Immunology in Pathology series.

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