T cell responses, Immunological memory, Secondary lymphoid tissue.
David’s research is focused on understanding the signals involved in the development and maintenance of T cell responses, in particular, the development of memory CD4 T cells which are essential for developing immunological memory. Immunological memory underpins our strategies of vaccination. Understanding how memory CD4 T cells are generated and maintained is crucial for improving upon our ability to both vaccinate and modulate unwanted self reactivity. CD4 T cell responses are initiated within secondary lymphoid tissues such as lymph nodes. Understanding how these structures are formed and also maintained is also important for a full understanding of the response.
Key areas of research:
Memory CD4 T cell survival and function
To improve our ability to modulate memory CD4 T cells, greater understanding of the signals involved is required. Since any given T cell clone is present in very low numbers within the host, it is imperative to track low numbers of antigen-specific T cells within our experimental approaches. Using a combination of techniques including MHCII tetramers and adoptive transfer of transgenic T cells, the responses of physiological cohorts of antigen specific CD4 T cells will be assessed.
Lymph node structure and function
The development of lymph nodes is dependent upon lymphoid tissue inducer cells, a specialised innate cell type that initiates the formation of these structures during embryonic development. Given that lymph node development is restricted to a window of embryonic development, it is somewhat surprising that these cells persist with adult lymph nodes, suggesting further functions within this tissue. Utilising different genetically modified mice, these cells can be removed from developed lymph nodes and the impact this has on lymph node function assessed.
Withers, D.R., Gaspal, F.M., Bekiaris, V., McConnell, F.M., Kim, M.-Y., Anderson, G., and Lane, P.J.L. (2011). Role of OX40 and CD30 in murine CD4 effector and memory function. Immunol Rev In press
Withers, D.R. (2011). Lymphoid tissue inducer cells. Curr Biol 21, R381-382.
Li, Y., Innocentin, S., Withers, D.R., Roberts, N.A., Gallagher, A.R., Grigorieva, E.F., Wilhelm, C., and Veldhoen, M. (2011). Exogenous Stimuli Maintain Intraepithelial Lymphocytes via Aryl Hydrocarbon Receptor Activation. Cell.
Gaspal, F.M., Withers, D., Saini, M., Bekiaris, V., McConnell, F.M., White, A., Yagita, H., Walker, L.S.K., Anderson, G., and Lane, P.J.L. (2011). Abrogation of CD30 and OX40 signals prevents autoimmune disease in FoxP3 deficient mice. J Exp Med 208 1579-1584, 1579-1584.
Kim, S., Han, S., Withers, D.R., Gaspal, F., Bae, J., Baik, S., Shin, H.C., Kim, K.S., Bekiaris, V., Anderson, G., et al. (2011). CD117(+) CD3(-) CD56(-) OX40L(high) cells express IL-22 and display an LTi phenotype in human secondary lymphoid tissues. Eur J Immunol 41, 1563-1572.
Withers, D.R., Jaensson, E., Gaspal, F., McConnell, F.M., Eksteen, B., Anderson, G., Agace, W.W., and Lane, P.J. (2009). The survival of memory CD4+ T cells within the gut lamina propria requires OX40 and CD30 signals. J Immunol 183, 5079-5084.