Objective
We hypothesize that self-metabolites produced by beta cells can activate MAIT cells, potentially representing a yet unexplored source of autorreactivity in T1D pathogenesis. Previous studies have focused on enumerating these cells, but none of them have interrogated their antigen specificities, a key step to understand their potential pathogenic role in T1D, and to leverage novel sources of antigens for immunotherapies.
Our goals and research questions are as follows:
GOAL 1: Identification of novel MR1 ligands.
RQ1: Which beta-cell related self-metabolites bind to MR1?
RQ2: Which type of responses do the identified MR1 ligands elicit in MAIT cells?
GOAL 2: Deep characterization of self-metabolite-specific MAIT cells in T1D.
RQ3: What are the antigen-specificities of MAIT cells in peripheral blood in T1D?.
RQ4: What are the features of T1D-relevant self-metabolite-specific MAIT cells?
RQ5: What is the relevance of T1D-relevant self-metabolite-specific MAIT cells in T1D tissues?
Background Rationale
Type 1 diabetes is an autoimmune disease where components of the immune system selectively destroy the insulin-producing beta cells of the pancreas. Several models have been proposed to try to elucidate the autoreactivity mechanisms taking place in the pancreas. In all cases, research has focused on antigens of peptide nature, such as insulin, GAD, IA-2 (among others) as well as neoantigens derived from them. However, another source of potential autoantigens exists, namely self-metabolites. Until just recently, the dogma was that all antigens recognized by T cells were mostly peptides derived from proteins or lipids. However, the discovery of mucosal associated invariant T (MAIT) cells has challenged this dogma. These cells recognize metabolites derived from the microbial metabolism of vitamin B, and recent studies suggest that they also recognize self-metabolites, although the identity of those remain to be elucidated. Interestingly, MAIT cell alterations are present in autoimmune diseases, including an increase of frequency in target tissues and a higher activation and cytotoxic status. This is also the case for Type 1 Diabetes. However, the identity of the metabolites recognized in T1D is completely unknown. Disentangling the antigen specificities of these altered MAIT cells in T1D would pave the way towards the development of novel antigen-specific immunotherapies which, given the nature of the MHC-presenting molecule, could be more universal than peptide-based ones, potentially easing the development and administration of these antigens.
Description of Project
Mucosal invariant T (MAIT) cells are a cell subset which lays within the innate-adaptive interface, and recognize metabolites. They constitute a frequent cell subset, and their activation triggers pro-inflammatory cytokine secretion, cytotoxic effector function, migration and proliferative expansion, inducing the death of target cells. They can also recognize cells presenting cancer-related metabolites and self-metabolites, although the identity of these metabolites remains to be elucidated.
Several factors also implicate these cells in autoimmune diseases, including their proinflammatory profile, wide-spread tissue distribution and effector-memory phenotype. Most studies found decreased MAIT cell frequency in blood, increased frequency in target tissues, and high activation and exhaustion phenotypes, in intestinal bowel disease, rheumatoid arthritis and multiple sclerosis, among others. This is also the case for T1D, where alterations in MAIT cell frequencies, together with a higher cytotoxic phenotype, were observed. However, none of these studies identified the beta-cell molecules that these cells were recognizing.
Hence, we propose that self-metabolites produced by stressed beta cells in T1D patients are recognized by MAIT cells, and such activation could be initiating and/or maintaining autoreactivity and damage to beta cells. For this, we will identify MAIT-activating MR1 ligands and then analyse the features of these cells in samples from T1D patients, unaffected siblings and healthy donors. Finally, we will examine their frequencies and features in blood and other tissues (nPOD). With this project we will shed light, for the first time, into the (auto)antigen specificities of MAIT cells in T1D and the role of self-metabolites in initiating and/or sustaining autoreactivity in T1D.
Anticipated Outcome
The Self-MAIT1D project will shed new light into autoreactivity mechanisms triggered by beta cell stress and driven by MAIT cells. Disentangling the antigen specificities of these altered MAIT cells in T1D would pave the way towards the development of novel antigen-specific immunotherapies which, given the nature of the MHC-presenting molecule, could be more universal than peptide-based ones, potentially easing the development and administration of these antigens.
Relevance to T1D
We postulate that MAIT cells recognize metabolites produced by beta cells in the T1D pancreas, and that such activation initiates and/or sustains inflammation and autoreactivity.
Thus, this proposal fully fits with JDRF’s Cures Research Strategy, where one of the highlighted rationales of T1D pathogenesis is that “beta cell stress occurs very early in the course of T1D and plays a role in the loss of beta cell function and mass, conceivably by triggering or potentiating the beta-cell specific autoimmune response”. Identifying these metabolites and understanding the relevance of MAIT cells in T1D would pave the way to developing novel therapies to disable the immune attack on beta cells, addressing JDRF’s Cures Research Strategy.
In particular, understanding the autoantigen specificities of MAIT cells in T1D, and analyzing their features will be important in order to identify opportunities for therapeutic intervention based upon metabolites presented by beta cells. Importantly, the monomorphic nature of MR1 versus the polymorphic nature of class I and II HLA molecules anticipates a more uniform antigen-specificity spectrum among patient groups, eliminating HLA-based inter-individual variability as a constraint in the translation of antigen-specific immunotherapies into clinic. Different reactivity patterns against different self-metabolites might also account for heterogeneity at the clinical level.
The combination of project, personal profile, network and resources make this project feasible, implementable and with high probability of delivering impactful results in the T1D field.
With this project we will shed light, for the first time, into the (auto)antigen specificities of MAIT cells in T1D. The impact of this project would also go beyond T1D research, as the MAIT field is a relatively nascent one, and although the literature shows that MAIT cells can indeed recognize self-components, the identity of such antigens remains elusive. Through the use of techniques not currently employed in antigen identification, such as virtual docking and high throughput drug discovery assays, we will speed up the identification of MAIT-activating self metabolites.