Below is a video and synopsis of the talk “Role Of T-Regulatory Cells In Immune Modulation” by Dr. Maria Roncarolo at the Vera Moulton Wall Center for Pulmonary Vascular Disease:
Summary
- Standard treatment of immune mediated diseases involves anti-inflammatory and immunosuppressive drugs. By doing this, you downregulate the physiological mechanism to counteract inflammation and adaptive immune responses to self-antigens. Almost all immunosuppressive drugs block T-regulatory cell induction and function.
- Tolerance is not a lack of immune response, it is just a different type of immune response that the immune system puts in place when we want to tolerize an antigen (self antigen or de novo antigens)
- There are no drugs out there that induce tolerance to a specific antigen that we want to down-regulate
- Overall goal: tone down specific immune responses without completely suppressing immunity.
- The immune system discriminates between self and nonself antigens, and between pathogenic and non-harmful antigens via tolerance. Central tolerance occurs in thymus, and peripheral tolerance occurs in the lymphoid tissues.
- T-regulatory (Treg) cells are an instrumental component of peripheral tolerance.
- T-regulatory cells play a key role in preventing pathology, and when you have a dysfunction in Treg specific for a specific antigen you have can end up with type I diabetes, rheumatoid arthritis, etc.
- However, Tregs can also play a detrimental role in some type of parasitic infections and viral infections. In Hepatitis C, Tregs are induced too early.
- CD4+ T Cells are only one subset of Tregs – there are NK regulatory cells, CD8, etc. And even within CD4+ there are 4 or 5 subsets of Tregs.
- Thymic derived FOXP3 are major players in maintaining tolerance to self
- Peripheral Tregs are induced in tissue
- IL10 is a master inducer of Tr1 cells
- In humans, every single activated T cell upregulates FOXP3. So FOXP3 is not a specific marker for Treg, especially if you have a lot of inflammation.
- FOXP3 Tregs are induced by IL2
- Rapamycin is permissive for Treg expansion and tolerance induction (it prevents Tregs from differentiating into Th17 cells)
- A simple way to cure a patient and induce tolerance is to shift the balance between the effector cells and the regulatory T cells: to give more Treg with FOXP3 with cell therapy.
- Clinical Trials:
- Infusion of freshly isolated CD4+CD25+FOXP3+ TReg cells after hematopoietic stem cell transplantation to prevent GvHD
- Showed safety and some efficacy in after double
- Infusion of ex vivo expanded CD4+CD25+FOXP3+ after double umbilical cord blood stem cell transplantation in adults to prevent GvHD, after treatment of acute or chronic GvHD, or after treatment of new onset Type I Diabetes
- All of these showed feasibility, safety, and some level of efficacy, but no dramatic effect.
- In all of these trials, the cells were polyclonal and not antigen specific, so you don’t know whether the lack of efficacy was due to the fact that you didn’t give the right cells.
- You have to distinguish between autoimmunity due to dysregulation of antigen specific Treg and genetic autoimmune disease where the dysregulation of the Treg is not antigen specific, but broad across the repertoire.
- IPEX Syndrome is an example of genetic autoimmune disease. FOXP3 mutations, neonatal onset, impaired Treg function, polyautoimmunity.
- In IPEX, Treg lineage commitment is preserved, but there is severe impairment in Treg function.
- Naive cells are skewed towards Th17
- FOXP3 mutations/deficiency targets tissue is gut, liver, and pancreas. CD25 deficiency target tissue is blood and sometimes even the lung.
- Tr1 cells may play a key role in diseases with a large inflammatory component where there is dysregulation of Th1 and Th2 cells.
- IL10 is the master regulator of Tr1, it is a key player in their induction and suppression.
- IL10 has a very strong anti inflammatory function, it inhibits macrophage, monocyte, and dendritic cell activation by inhibiting not only a number of costimulatory molecule expression but by downregulating inflammatory cytokines and chemokines. And they upregulate natural anti inflammatory molecules in the body including IL1 receptor antagonist.
- Mice with IL10 or IL10 receptor knockout show hypersensitivity to LPS, exaggerated inflammatory reactions, contact hypersensitivity, and spontaneous IBD.
- IL10 and TGF beta downregulate inflammatory molecules produced by dendritic cells and convert dendritic cells into regulatory T cells, and produce GZB which kills myeloid APC’s and thus downregulates T cell priming.
- CD4+FOXP3+ Tregs induce tolerance and act locally in the target organ. Whereas Tr1 cells maintain antigen specific stable long-term tolerance and reside in the spleen.
- FOXP3 are akin to firefighters, and Tr1 are the sheriff/patrols.
