A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice

Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

Abstract: The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report

Abstract: The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients

Unconventional functions of MR1 restricted T-cells

The non-polymorphic MHC class I-related protein 1 (MR1) is an antigen presenting receptor that displays endogenous or microbial-derived metabolic intermediates. The commensal antigens, such as intermediates of the riboflavin synthesis pathway, are the most well understood so far and, these are known to activate mucosal associated invariant T (MAIT) cells. MAIT cells have been widely studied for their innate-like properties and, their strong pro-inflammatory and anti-microbial functions in response to TCR-dependent and TCR-independent signalling. These characteristics confers them with an important, but so far unclear, role in mucosal immunity and autoimmune diseases. Other non-MAIT MR1-restricted T (MR1T) cells have shown specificity to both commensal and endogenous antigens; however, we are still far from understanding the diversity in their functions, phenotype, antigenic specificity and, TCR repertoire. In this thesis, we used RNAseq analysis to dissect the downstream effects of TCR-dependent and TCR-independent signals on their own and in combination. Our experiments revealed that while the inflammatory responses are tightly regulated and primarily driven by TCR-independent signalling, TCR-mediated activation elicit other unexpected functions related to homeostasis and tissue repair. These data provide a deeper insight on how MAIT cells balance inflammatory and protective functions at barrier sites under constant exposure to the microbiota. We also explored MR1 as a target molecule for TCR-based immunotherapy against cancer disease. We hypothesised that the endogenous metabolic intermediates could be antigens of interest for the specific targeting of cells undergoing metabolic stress, such as transformed cancerous cells. In this thesis, we collaborated with Immunocore, a leader in TCR-based immunotherapies, to validate the role of MR1T cells in cancer disease and analysed the specificity of 2 new autoreactive MR1T cells. This work also proposes new methods to accelerate the discovery of antigens and TCR sequences in the unexplored field of MR1T cells