Regulation of adaptive immunity
Regulation of adaptive immunity studies the mechanisms that control autoimmunity and antiviral immunity. By maintaining the immune system in equilibrium, the body is protected from autoimmune diseases such as type 1 diabetes and from excessive or undesired responses against viruses. More precisely, the group is investigating how PTPN22, a gene associated with autoimmunity, controls virus-specific T cell responses, characterizing the contribution of T follicular helper and regulatory T cells - two T cell subsets that aid and control antibody responses-respectively - in the development of autoimmunity. The research group is also addressing how regulatory T cells control antiviral immunity, and vice versa, how viral infections impede regulatory T cell function and stability. The aim is to aid in the design of efficient and safe tolerogenic approaches to control autoimmunity without compromising host antiviral immune defence.
- PTPN22 and the regulation of antiviral T cell responses.The protein tyrosine phosphatase non-receptor type 22 R620W (PTPN22*W) allele is a major risk factor for the development of several autoimmune diseases such as type 1 diabetes and rheumatoid arthritis. The mechanism by which PTPN22 acts as an autoimmune susceptibility locus is still ill-defined. PTPN22*W encodes for a gain-of-function variant that alters T-cell receptor (TCR), B-cell receptor (BCR) and Toll-like receptor (TLR) signaling suggesting that it might contribute to autoimmune disease development by modulating adaptive and innate immune responses. It is postulated that certain autoimmune-susceptibility genes might alter resistance to infection. Since environmental factors, such as viral infections are considered triggers of autoimmune diseases, it is possible that PTPN22 influences the progression to autoimmunity by altering the response to pathogens. Indeed, as we and others found, PTPN22 plays a key role in controlling antiviral immune responses. Here, by utilizing PTPN22 knockout mice, we address how PTPN22 modulates antiviral cytotoxic T cell responses. The data obtained from this study may provide evidence for the role of PTPN22 in mediating “environmental” influence on the progression to autoimmunity.
- Follicular helper and regulatory T cells in the development of autoimmunity. T follicular helper (Tfh) cells are a subset of CD4 T cells highly specialized in aiding antibody responses in germinal centres (GCs). GCs are microanatomical structures where somatic B-cell receptor hypermutation and affinity maturation occur. Because Tfh cells are necessary for the GC reaction, they are crucial for the generation of affinity-matured memory B cells and long-lived plasma cells. It is becoming clear that the number and function of Tfh cells are important factors for effective antibody responses, since decreased number or insufficient function of Tfh cells contributes to immunodeficiency characterized by reduced or complete lack of antibody production. On the flip-side, hyperactivation or aberrant Tfh cellularity may cause autoimmunity. To safeguard the function of Tfh cells, T follicular FOXP3+ regulatory (Tfr) cells exert a pivotal function in preventing excessive GC reactions and autoantibody (AAb) production. Thus, Tfr cells restrain the B cell helper activity of Tfh cells and are considered critical for optimal generation, function and termination of GC responses, which could otherwise lead to autoimmunity. The mechanism by which Tfr cells control the effect of Tfh cells on B cells is currently unclear, while some reports support that they share several of the suppressive properties retained by conventional, non-Tfr regulatory (Treg) cells. In our group we study: 1) the transcriptome landscape of human Tfr cells and the mechanism by which Tfr cells control GC responses, 2) the number, phenotype and function of Tfh and Tfr cells in the peripheral blood, spleen and pancreatic lymph nodes (pancLN) of patients with type 1 diabetes (T1D) versus healthy controls.
- Regulatory T cell stability and safety during viral infection. T cells are crucial in controlling immunity and tolerance. Given their important role in the induction and maintenance of tolerance, there is great interest in their therapeutic use for patients with autoimmunity. Over the last decade enormous progress has been made toward the development of large numbers of regulatory T cells by good manufacturing practice (GMP). However, this objective is thwarted by concerns regarding the stability and safety of regulatory T cells, especially in the course of a viral infection. Regulatory T cells display a certain level of functional plasticity that derives from their ability to sense the environment and adjust their gene expression. This functional plasticity is essential for the immune system to appropriately respond toward pathogens. While regulatory T cell plasticity is vital for the proper function of the immune system, it also poses a potential threat. Given the autoreactive nature of regulatory cells for example, there are concerns they might promote autoimmunity. On the contrary, there are reports showing that regulatory T cells are able to utilize molecular mechanisms that guarantee their lineage stability also under inflammatory conditions. In this case however, there are concerns that tolerance to pathogens i.e. to viruses may be induced with detrimental impact for the patient’s health. By utilizing a mouse model of pancreatic islet transplantation, we address the stability and safety of regulatory T cells therapy in the course of an acute viral infection.
Jofra T, Di Fonte R, Hutchinson TE, Dastmalchi F, Galvani G, Battaglia M, Salek-Ardakani S, Fousteri G. Protein tyrosine phosphatase PTPN22 has dual roles in promoting pathogen versus homeostatic-driven CD8 T-cell responses. Immunol Cell Biol. 2017 Feb;95(2):121-128.
Cantarelli E, Citro A, Pellegrini S, Mercalli A, Melzi R, Dugnani E, Jofra T, Fousteri G, Mondino A, Piemonti L. Transplant site influences the immune response after islet transplantation: bone marrow vs liver. Transplantation 2017 May;101(5):1046-1055.
Fousteri G, Ippolito E, Ahmed R, Hamad AR. Beta-cell specific autoantibodies: are they just an indicator of type 1 diabetes? Curr Diabetes Rev. 2017;13(3):322-329.
Hamad AR, Ahmed R, Donner T, Fousteri G. B cell-targeted immunotherapy for type 1 diabetes: What can make it work? Discov Med. 2016. 21:213-219.
Di Fonte R, Baronio M, Plebani A, Lougaris V, Fousteri G. Reduced germinal center follicular helper T cells but normal follicular regulatory T cells in the tonsils of a patient with a mutation in the PI3KR1 gene. Clin Immunol. 2016 Mar;164:43-4.
Fousteri G, Jofra T, Di Fonte R, Battaglia M. Combination of an antigen-specific therapy and an immunomodulatory treatment to simultaneous block recurrent autoimmunity and alloreactivity in non-obese diabetic mice. PLoS One. 2015. 10:e0127631.
Fousteri G, Jofra T, Di Fonte R, Gagliani N, Morsiani C, Stabilini A, Battaglia M. Lack of the protein tyrosine phosphatase PTPN22 strengthens transplant tolerance to pancreatic islets in mice. Diabetologia 2015. 58:1319-1328.
Fousteri G, Jofra T, Di Fonte R, Kuka M, Iannacone M, Battaglia M. PTPN22 controls virally-induced autoimmune diabetes by modulating cytotoxic T lymphocyte responses in an epitope-specific manner. Clin Immunol. 2015. 156:98-108.
Sarikonda G, Fousteri G*, Sachithanantham S, Miller JF, Dave A, Juntti T, Coppieters KT, von Herrath M. BDC12-4.1 T-cell receptor transgenic insulin-specific CD4 T cells are resistant to in vitro differentiation into functional Foxp3+ T regulatory cells. PLoS One 2014;9(11): e112242.
Fousteri G, Jofra T, Debernardis I, Stanford SM, Laurenzi A, Bottini N, Battaglia M. The protein tyrosine phosphatase PTPN22 controls forkhead box protein 3 T regulatory cell induction but is dispensable for T helper type 1 cell polarization. Clin Exp Immunol. 2014 Oct;178(1):178-89.