B cells, T cells, generation and maintenance of adaptive responses, infection, vaccination, immune homeostasis, immune modulation
Our work aims to understand how infection changes who we are as individuals. Our work has a particular focus on how infection can educate the immune system and the specific elements and cells of the immune system that respond to pathogens. An exciting consequence of this work is that by comparing how we react to the whole pathogen or to individual components of the pathogen we can generate new vaccines to infections and new treatments to infectious and non-infectious diseases.
Our research uses in vivo models of infection to study how infection and vaccination modifies immune homeostasis, with a particular emphasis on adaptive immunity. Relating these changes to bacterial clearance helps identify how infections are controlled and how vaccines function. Furthermore, understanding the relationship between host and pathogen helps identify novel approaches to exploit bacteria and their components as prophylactics and therapeutics in infectious and non-infectious diseases (Fig. 1).
Examples of current themes ongoing in the laboratory include:
1. The development of vaccines against non-typhoidal Salmonella and the potential of B1b cells as targets for vaccination
2. How T and B cell responses are regulated after infection and vaccination
3. How lymphopoiesis is regulated in the thymus and bone marrow during infection
4. How bacteria and their components immunomodulate the host during infectious and non-infectious disease
5. How multiple and co-infections impact upon host homeostasis and immune function
6. How dormant tuberculosis infections in humans are maintained
Such investigations require studies of immune homeostasis in multiple anatomical locations concurrently, the different cellular subsets involved and the kinetics of these events (Fig. 2)
Though this work is performed primarily in the context of infection and vaccination, with a particular focus on adaptive immunity and its direction by the innate immune system, the principles allow us to investigate how non-infectious disease impacts on the host.
Our work has shown that the immune system responds differently to the same antigen when presented in different immunological contexts and in different anatomical compartments. This is important since it means we can modify the response to an antigen or promote a particular host function simply by altering how we deliver antigen to the immune system. This capacity to modulate the host response to a pathogen or a component of a pathogen or a vaccine underlies our translational work (see publications). Lastly, using this knowledge we can exploit our findings to maintain and improve health as we age through directing and stimulating beneficial, long-term immune responses. Collectively, our work therefore helps understand how we can improve immunity to infectious and non-infectious disease.
Ross E.A., Coughlan R.E., Flores-Langarica A., Lax S., Nicholson J., Marshall J.L., Bobat S., Hitchcock J., White A., Jenkinson W.E., Desanti G.E., Khan M., Henderson I.R., Lavery G.G., Buckley C.D., Anderson G. and Cunningham A.F. (2012). Thymic function is maintained during Salmonella-induced atrophy and recovery. Journal of Immunology, In press
Ross E.A., Coughlan R.E., Flores-Langarica A., Bobat S., Hussain K., Charlesworth J., Abhyankar N., Marshall J.L., Hitchcock J., Gil-Cruz C., López-Macías C., Khan M., Watson S.P., MacLennan I.C.M., Buckley C.D., and Cunningham A.F. (2011). CD31 is required on CD4+ T cells to promote T cell survival and clearance of Salmonella infection. Journal of Immunology, 187: 1553-1565
Flores-Langarica A., Marshall J.L., Bobat S., Mohr E., Hitchcock J., Ross E.A., Coughlan R.E., Khan M., Van Rooijen N., Henderson I.R., MacLennan I.C.M., and Cunningham A.F. (2011). Recruited monocyte-derived dendritic cells collaborate with conventional DC to prime Th1 responses to Salmonella. EuropeanJournal of Immunology, 41: 2654-2665.
Bobat S., Flores-Langarica A., Hitchcock J., Marshall J.L., Kingsley R.A., Goodall M., Gil-Cruz C.,Serre K., Leyton D.L., Letran S.E., Gaspal F., Chester R., Dougan G., López-Macías C., Henderson I.R., Alexander J., MacLennan I.C.M., and Cunningham A.F. (2011). Soluble flagellin, FliC, induces an antigen-specific Th2 response, yet promotes T-bet-regulated Th1 clearance of Salmonella Typhimurium infection. EuropeanJournal of Immunology, 41: 1606-1618
Lee S.K., Rigby R.J., Zotos D., Tsai L.M., Kawamoto S., Marshall J.L., Ramiscal R.R., Chan T.D., Gatto D., Brink R., Yu D., Fagarasan S., Tarlinton D.T., Cunningham A.F. and C.G. Vinuesa. (2011). B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. Journal of Experimental Medicine, 208: 1377-1388.
MacLennan C.A., Gilchrist, J.J., Gordon M.A., Cunningham A.F. Cobbold M., Goodall M., Kingsley R.A., van Oosterhout J.J.G., Msefula C.L., Mandala W.L. Leyton D.L. Marshall J.L., Gondwe E.N., Bobat S., López-Macías C., Doffinger R., Henderson I.R., Zijlstra E.E., Dougan G., Drayson M.T., MacLennan I.C.M., and Molyneux M.E. (2010). Cobbold M., Goodall M., Kingsley R.A., van Oosterhout J.J.G., Msefula C.L., Mandala W.L. Leyton D.L. Marshall J.L., Gondwe E.N., Bobat S., López-Macías C., Doffinger R., Henderson I.R., Zijlstra E.E., Dougan G., Drayson M.T., MacLennan I.C.M., and Molyneux M.E. (2010). Dysregulated humoral immunity to nontyphoidal Salmonella in HIV- infected African adults. Science. 328: 508-512.
Gil-Cruz C., Bobat S., Marshall J., Kingsley R.A., Ross E.A., Henderson I.R., Leyton D.L., Coughlan R.E., Khan M., Jensen K.T., Buckley C.D., Dougan G., MacLennan I.C.M., López-Macías C., and Cunningham A.F. (2009). The porin OmpD from non-typhoidal Salmonella is a key target for a protective B1b cell antibody response. Proceedings of the National Academy of Sciences USA. 106: 9803–9808
Cunningham A. F., Gaspal F., Serre K., Mohr E., Henderson I. R., Scott-Tucker A., Khan M., Toellner K.M., Lane P.J., and I.C. MacLennan. (2007). Salmonella induces a switched antibody response without germinal centers that impedes the extracellular spread of infection. Journal of Immunology. 178: 6200-07