The role of CTLA-4 in health and autoimmune disease

FOXP3+ regulatory T (Treg) cells are powerful regulators of the immune system, as shown by the development of multi-organ autoimmunity in mice and men upon loss or dysfunction of these cells. Whilst Treg cells are vital to control normal immune responses, they are also involved in the development of autoimmunity and the failure to combat cancer. Cytotoxic T lymphocyte antigen-4 (CTLA-4) is an important regulator of adaptive immune responses and vital for the function of Treg cells, as demonstrated by loss of function studies that result in similar autoimmunity as that caused by loss of Treg cells.

The broad aim of this thesis was to gain a deeper understanding of how CTLA-4 mediated tolerance operates both in health and in autoimmune disease, as its role in the adult immune system remains ill-defined. Therefore, in study I, we developed a novel system that allows for the inducible depletion of CTLA-4. Loss of CTLA-4 in adulthood unleashed T cell, but especially Treg cell homeostasis, resulting in multi-organ lymphocytic infiltrations that however did not progress to fatal autoimmunity and affected different organs than congenic CTLA-4 deficiency did, which implies a role for CTLA-4 in thymic T cell selection. Furthermore, we could show that loss of CTLA-4 can have both disease promoting as well as protective effects, depending on the type of autoimmunity as well as the inducing agent, depicting the need for context specific studies. Thus, in study II, we focused on collageninduced arthritis (CIA) and found that CTLA-4 regulated all stages of disease as well as disease spreading, albeit without affecting heterogeneous T or B cell responses. Autologous responses were however controlled by CTLA-4 and loss of CTLA-4 could break pre-established T cell tolerance to type-II collagen (CII). Furthermore, we found that CTLA-4 on conventional T cells limited the priming of autoreactive T cells, whereas Treg cell specific CTLA-4 was necessary to control the inflammatory tissue attack. In study III, we analyzed CII-specific T cells and found that CTLA-4 could induce tolerance in individuals with an inherent T cell predisposition to joint reactivity. These tolerized, CII-reactive T cells were found in high frequencies in the liver and transfer of liver lymphocytes could induce tolerance in otherwise susceptible hosts. Further studies are needed to elucidate if tolerance is induced in the liver or whether tolerized T cells accumulate in this organ, but it opens exciting possibilities for research aiming to induce tolerance in arthritis patients. In study IV, we used mice defective in reactive oxygen species that suffer from an increased susceptibility to infections, to show that increased susceptibility to autoimmunity is not merely a consequence of these infections but is a separate phenomenon.

Taken together, our data reveal the complex nature of CTLA-4 mediated regulation and the necessity to study antigen-specific responses. They also demonstrate the immensely powerful tolerance inducing abilities of CTLA-4, even in the face of enhanced self-reactivity. This increased understanding will be of importance for finding novel treatment strategies for patients suffering from autoimmunity.

List of scientific papers

I. Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood. Katrin Klocke, Shimon Sakaguchi, Rikard Holmdahl and Kajsa Wing. Proc Natl Acad Sci U S A. 2016 Apr 26;113(17):E2383-92.
https://doi.org/10.1073/pnas.1603892113

II. CTLA-4 expressed by FOXP3+ Treg cells prevents inflammatory tissue attack and not T cell priming in arthritis. Katrin Klocke, Rikard Holmdahl and Kajsa Wing. Immunology. 2017. [Accepted]
https://doi.org/10.1111/imm.12754

III. Collagen reactive T cells accumulate in the liver and protect from arthritis. Katrin Klocke, Rikard Holmdahl and Kajsa Wing. [Manuscript]

IV. Germ-free mice deficient of reactive oxygen species have increased arthritis susceptibility. Kajsa Wing, Katrin Klocke, Annika Samuelsson and Rikard Holmdahl. Eur J Immunol. 2015 May;45(5):1348-53.
https://doi.org/10.1002/eji.201445020