ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Quantifying T-cell responses in complex disorders of immune dysregulation (#182)

Anthony Farchione 1 2 , Jessica Tempany 1 2 , Julika Neumann 1 2 , David Vremec 1 2 , Charlotte Slade 1 2 3 , Jo Douglass 1 2 3 , Jason Tye-Din 1 2 3 , Susanne Heinzel 1 2 , Phil Hodgkin 1 2 , Vanessa Bryant 1 2
  1. Walter and Eliza Hall Institute of medical research, Parkville, VICTORIA, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia
  3. Department of Clinical Immunology & Allergy, The Royal Melbourne Hospital, Parkville, Victoria, Australia

We have developed a standardised, quantitative, functional assay of human T-cell responses to measure the sensitivity and integration of T-cell activation signals. By measuring cell division, death, differentiation and division burst size (division destiny) in response to controlled in vitro stimuli we can uncover and identify differences in the innate programming of T cells and their capacity to mount an effective response. This assay was validated using CD4+ and CD8+ T cells from unrelated healthy donors and applied to investigate responses from individuals with complex disorders of immune dysregulation.

A healthy immune response is governed by the coordinated effect of cell proliferation, division cessation and cell death. Disruptions to immune responses in individuals with immune dysregulation disorders lead to susceptibility to infections and/or autoimmunity. Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder typically characterised by reduced serum immunoglobulin and susceptibility to infections but is often accompanied by diverse autoimmune complications involving T-cell dysregulation. Similarly, Coeliac disease is a T-cell disorder involving dysregulated T-cell responses when gluten is consumed, resulting in inflammation and damage to the gastrointestinal tract. Both immune dysregulation disorders impose the need to investigate T-cell responses to understand and treat these conditions.

Our quantitative in vitro assay evaluated the response of activated human T cells in CVID and Coeliac individuals and identified functional differences likely contributing to underlying immune dysregulation. Naïve CD4 and CD8 T-cell responses showed remarkable variability in T-cell proliferative responses to stimuli, with a range of hypo and hypersensitivity that was not observed in healthy donor T cells.  Strikingly, naïve T cells from Coeliac patients demonstrated a significant proliferative defect in response to T-cell stimuli, potentially via aberrant IL-2 production. These findings propose new avenues for detecting cell-specific functional abnormalities in immunodeficiencies and autoimmunity at a personalised level.