Understanding immunological tolerance is an important step towards developing new therapies for diseases that do not respond well to current treatments. Put simply, immunological tolerance can be described as the ability of the immune system to recognise a substance (or antigen) but not to respond to it. For instance, our immune system usually will not attack tissues and cells of our own body, but can recognise invasion by an infectious agent and attempt to destroy it. This decision making process is highly sophisticated but still needs to be understood.
A complete understanding of immunological tolerance will allow us to have exquisite control over the immune system, switching responses on and off, according to the needs of the patient. For patients with autoimmune disease (e.g., multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus and type 1 diabetes) manipulating immunological tolerance could allow us to switch off the damaging immune response that is inappropriately targeting self tissues. Similar techniques could be used to switch off the immune responses underlying transplant rejection and even allergy. On the other side of the coin, we could also boost immune responses for difficult to treat disease, e.g., cancer. The important aspect of such manipulations is that they only specifically affect the immune response of concern, e.g., in type 1 diabetes only the destructive immune response targeting pancreatic islet cells would be switched off, leaving the rest of the immune system intact and able to fight off infection and other challenges to the individual.
My research interest is in understanding the molecular processes important for immunological tolerance
I am interested in soluble CTLA-4 as a candidate molecule that influences the decision-making process underlying immunological tolerance. Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is an important molecule found primarily on the surface of T lymphocytes or T cells. As a membrane-bound protein it is important for regulating the intensity of T cell responses. In particular, a form of T cell termed a regulatory T cell (Treg) requires CTLA-4 to control immune responses.
The soluble form of CTLA-4 (sCTLA-4) is a natural genetic variant of the membrane-bound form but can be secreted by the cell that makes it. Although it less well-studied than the membrane-bound form of the molecule, there have been some very interesting observations. Ueda et al, (2003) performed an extensive study identifying single nucleotide polymorphisms (SNPs) within the ctla4 gene region that were associated with increased susceptibility to developing autoimmune diseases including Grave's disease and type 1 diabetes. One such SNP, called CT60, was associated not only with increased disease susceptibility but reduced production of sCTLA-4.
Here at the University of Aberdeen we have developed a monoclonal antibody, JMW-3B3, that is specific only for human sCTLA-4 – it does not bind to the membrane-bound form of CTLA-4. Using this antibody as a research tool we are able to look specifically at the function of sCTLA-4 and have already made a number of interesting observations. It is likely that the molecule is produced by a particular T cell subset and is very important for regulating the intensity of antigen-specific immune responses. Blockade of its function with the antibody significantly increases both cell proliferation and production of the effector cytokine interferon-γ.
HOW SOLUBLE CTLA-4 COULD INHIBIT ANTIGEN-SPECIFIC IMMUNE RESPONSES
There are a number of mechanisms by which Treg might utilise natural sCTLA-4 to regulate immune responses. 1. Simple blockade of T cell co-stimulation. T cells require two signals for full activation – engagement of the T cell receptor (TCR) with a peptide antigen presented by MHC molecules on antigen presenting cells (APC), and secondly, engagement of CD28 on the T cell with B7 ligands on the APC. sCTLA-4 also binds B7 ligands so can outcompete CD28 and disrupt this second signal. 2. Indoleamine 2,3 dioxygenase (IDO) is a fascinating enzyme system that catabolises the amino acid tryptophan. In turn, this establishes a microenvironment that is deleterious for robust effector T cell responses. sCTLA-4 can induce IDO production and can therefore inhibit T cell responses using this system. 3. A recent study demonstrated that a recombinant form of sCTLA-4 (called CTLA4-Ig) can induce nuclear localisation of the FoxO3 transcription factor, which in turn inhibits production of cytokines including IL-6, thereby constraining T cell survival. 4. IL-10 is a well-characterised immunosuppressive cytokine. Our studies have indicated that sCTLA-4 is produced predominantly by cells that also secrete IL-10 and further, sCTLA-4 can itself induce increased production of IL-10 in an antigen-dependent manner. Other mechanisms may also be important.
1. Oaks, M.K., and K.M. Hallett. 2000. Cutting edge: a soluble form of CTLA-4 in patients with autoimmune thyroid disease. J. Immunol. 164:5015-5018.
2. Magistrelli, G., P. Jeannin, N. Herbault, A. Benoit De Coignac, J.F. Gauchat, J.Y. Bonnefoy, and Y. Delneste. 1999. A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur. J. Immunol. 29:3596-3602.
3. Ueda, H., J.M. Howson, L. Esposito, J. Heward, H. Snook, G. Chamberlain, D.B. Rainbow, K.M. Hunter, A.N. Smith, G. Di Genova, M.H. Herr, I. Dahlman, F. Payne, D. Smyth, C. Lowe, R.C. Twells, S. Howlett, B. Healy, S. Nutland, H.E. Rance, V. Everett, L.J. Smink, A.C. Lam, H.J. Cordell, N.M. Walker, C. Bordin, J. Hulme, C. Motzo, F. Cucca, J.F. Hess, M.L. Metzker, J. Rogers, S. Gregory, A. Allahabadia, R. Nithiyananthan, E. Tuomilehto-Wolf, J. Tuomilehto, P. Bingley, K.M. Gillespie, D.E. Undlien, K.S. Ronningen, C. Guja, C. Ionescu-Tirgoviste, D.A. Savage, A.P. Maxwell, D.J. Carson, C.C. Patterson, J.A. Franklyn, D.G. Clayton, L.B. Peterson, L.S. Wicker, J.A. Todd, and S.C. Gough. 2003. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature 423:506-511.
4. Grohmann, U., C. Orabona, F. Fallarino, C. Vacca, F. Calcinaro, A. Falorni, P. Candeloro, M.L. Belladonna, R. Bianchi, M.C. Fioretti, and P. Puccetti. 2002. CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat. Immunol. 3:1097-1101.
5. Dejean, A.S., D.R. Beisner, I.L. Ch'en, Y.M. Kerdiles, A. Babour, K.C. Arden, D.H. Castrillon, R.A. DePinho, and S.M. Hedrick. 2009. Transcription factor Foxo3 controls the magnitude of T cell immune responses by modulating the function of dendritic cells. Nat. Immunol. 10:504-513.