University College London (UCL)
Royal Free Hospital
The immune system has to strike a delicate balance. Responses that are too weak or too slow leave us vulnerable to infections and cancer. One the other hand, over-zealous immune responses can lead to the development of autoimmune diseases, where tissues of our own body become targets of the immune attack. This is exemplified by the immune-mediated damage to the pancreas in type 1 diabetes, the joints in rheumatoid arthritis and the nervous system in multiple sclerosis. Our group has a particular interest in the autoimmune attack on the pancreatic beta cells that occurs in type 1 diabetes. The incidence of type 1 diabetes is rising at a remarkable rate, particularly in children under the age of 5. The overarching aim of the Walker lab is to understand why certain individuals develop an immune response against pancreatic islet antigens that lead to this condition. We believe that a more precise understanding of the mechanisms underlying this immune response will provide new clues about how to halt the disease process. Research in the Walker lab focuses in particular on the areas highlighted below.
A major mechanism for controlling T cell responses involves the system of costimulation whereby T cells need to receive a second signal through their costimulatory receptor, CD28, in order to ensure full activation after encounter with antigen. The requirement for costimulation imposes an additional safeguard on the T cell activation step, making it more likely that this only occurs in circumstances where launching an immune response is appropriate. Microbes often bear molecules that upregulate the ligands for CD28, making costimulation more likely during infection. CD28 has a homologue, called CTLA-4, that is an important negative regulator of T cell activation. In mice (1, 2) or humans (3, 4) that have defective CTLA-4 function, T cells become hyperactivated leading to an immune dysregulation syndrome. CTLA-4 is highly expressed on a population of cells with immunosuppressive function termed Regulatory T cells (Treg) (5, 6). In animal models, injecting Treg can prevent or even cure autoimmune diseases so there is considerable interest in understanding how these cells work.Our research has shown that Treg that are deficient for CTLA-4 are unable to control diabetes in a murine adoptive transfer model (7). In close collaboration with the group of Professor David Sansom, we have identified a novel molecular mechanism for CTLA-4 function (8). We found that CTLA-4 is able to downregulate expression of the ligands for CD28, thereby limiting T cell costimulation and activation. Although CTLA-4 is expressed at high levels on Treg, it is also expressed on conventional T cells and can play a regulatory role in these cells too (9). Our group is interested in unraveling how CTLA-4 and Treg act to maintain immune homeostasis and how their aberrant function may lead to autoimmunity.
The phenotype of the T cells that cause type 1 diabetes is currently unclear. The Walker lab is pursuing this question using mouse models of diabetes in combination with analysis of T cells isolated from the blood of type 1 diabetes patients (in collaboration with Dr Miranda Rosenthal at the Royal Free London NHS Foundation Trust). We have recently uncovered evidence that memory T cells from type 1 diabetes patients have a signature for follicular-helper T cell (TFH) differentiation (10). Cells with a TFH phenotype have previously been associated with autoimmunity (11) and intriguingly the development of these cells can be influenced by the CD28 and CTLA-4 pathways (12). We are interested in studying how the type of T cell differentiation that occurs in type 1 diabetes influences disease pathogenesis. In this regard, TFH cells are known to produce large amounts of the cytokine IL-21 which we have shown can have a profound effect on Treg function (13). Overexpression of this cytokine may therefore interfere with our natural immunosuppressive mechanisms and lower our defenses against autoimmunity.
While the importance of T cells in driving type 1 diabetes is unquestioned, our group has become increasingly interested in additional cell types that enter the pancreas alongside the T cells and that may help or hinder the disease process. B cells can be seen to infiltrate the pancreatic islets of both mice and humans with type 1 diabetes and B cell depletion can inhibit diabetes (reviewed in (14)). We are interested in dissecting how particular B cell populations, including B1 cells, contribute to the disease process. We have also begun to identify additional cellular players within inflamed pancreatic islets, including populations of innate lymphoid cells. The role of these additional cell types within the pancreatic infiltrate is currently being investigated. By learning about the cellular interactions that modulate the autoimmune attack we hope to discover new ways of interrupting the disease process.
1. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. 1995. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3: 541-7
2. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW. 1995. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270: 985-8
3. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schaffer AA, Gruning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Seneviratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LS, Sansom DM, Grimbacher B. 2014. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature Medicine 20: 1410-6
4. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G. 2014. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345: 1623-7
5. Read S, Malmstrom V, Powrie F. 2000. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. Journal of Experimental Medicine 192: 295-302
6. Takahashi T, Tagami T, Yamazaki S, Uede T, Shimizu J, Sakaguchi N, Mak TW, Sakaguchi S. 2000. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. Journal of Experimental Medicine 192: 303-10
7. Schmidt EM, Wang CJ, Ryan GA, Clough LE, Qureshi OS, Goodall M, Abbas AK, Sharpe AH, Sansom DM, Walker LS. 2009. CTLA-4 controls regulatory T cell peripheral homeostasis and is required for suppression of pancreatic islet autoimmunity. Journal of Immunology 182: 274-82
8. Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, Schmidt EM, Baker J, Jeffery LE, Kaur S, Briggs Z, Hou TZ, Futter CE, Anderson G, Walker LS, Sansom DM. 2011. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. Science 332: 600-3
9. Walker LS. 2013. Treg and CTLA-4: Two intertwining pathways to immune tolerance. Journal of Autoimmunity 45: 49-57
10. Kenefeck R, Wang CJ, Kapadi T, Wardzinski L, Attridge K, Clough LE, Heuts F, Kogimtzis A, Patel S, Rosenthal M, Ono M, Sansom DM, Narendran P, Walker LS. 2015. Follicular helper T cell signature in type 1 diabetes. The Journal of Clinical Investigation 125: 292-303
11. Linterman MA, Rigby RJ, Wong RK, Yu D, Brink R, Cannons JL, Schwartzberg PL, Cook MC, Walters GD, Vinuesa CG. 2009. Follicular helper T cells are required for systemic autoimmunity. Journal of Experimental Medicine 206: 561-76
12. Wang CJ, Heuts F, Ovcinnikovs V, Wardzinski L, Bowers C, Schmidt EM, Kogimtzis A, Kenefeck R, Sansom DM, Walker LS. 2015. CTLA-4 controls follicular helper T-cell differentiation by regulating the strength of CD28 engagement. Proc Natl Acad Sci U S A 112: 524-9
13. Attridge K, Wang CJ, Wardzinski L, Kenefeck R, Chamberlain JL, Manzotti C, Kopf M, Walker LS. 2012. IL-21 inhibits T cell IL-2 production and impairs Treg homeostasis. Blood 119: 4656-64
14. Chamberlain JL, Attridge K, Wang CJ, Ryan GA, Walker LS. 2011. B cell depletion in autoimmune diabetes: insights from murine models. Expert Opinion on Therapeutic Targets 15: 703-14