T-cell phenotype and arginine deprivation in critical illness

Abstract

The global burden of critical illness is rising and there is an urgent need to develop new therapies. The high incidence of secondary infections in this group suggests a failure of antigen-specific T-cell immunity. The amino acid arginine is important for T-cell proliferation, and the enzyme arginase-1 mediates arginine deprivation in disease states. T-cell phenotypic and functional changes with arginine deprivation are poorly characterised, and it is unknown whether they are seen in critical illness.

Flow cytometry was used to characterise antigen-specific T-cell phenotype and function after arginine deprivation in vitro. The same approach was utilised to determine whether these phenotypic changes could also be observed in two forms of critical illness – sepsis and out-of-hospital cardiac arrest (OHCA).

I showed arginine-deprived antigen-specific CD8 T-cells proliferate at reduced capacity in vitro but retain normal effector function. Arginine-deprived T-cells showed reduced CD3ζ expression and altered coinhibitory receptor expression. Both sepsis and OHCA were arginine-deprived states, with raised myeloid cell arginase-1 and T-cell features of arginine deprivation (reduced CD3ζ and raised CD98). Myeloid arginase levels were higher in sepsis and OHCA patients who developed nosocomial infections. T-cells show increased expression of multiple coinhibitory receptors, with CD8 T-cell PD-1 expression associated with mortality in sepsis and nosocomial infection in OHCA. Raised CD4 Treg coinhibitory receptor expression in sepsis was associated with nosocomial infection. Finally, T-cells in critical illness showed reduced glycolysis and OXPHOS, and increased fatty acid metabolism. Reduced flux through T-cell metabolic pathways was associated with nosocomial infections in sepsis.

My findings suggest arginase-mediated arginine deprivation in critical illness might be associated with secondary infections. The increased coinhibitory receptor expression potentially suggests T-cell exhaustion, which may contribute to susceptibility to secondary infections. Altered T-cell metabolism in sepsis is associated with secondary infections and further mechanistic understanding could identify new pathways to target therapeutically.

Date of Award	30 Sept 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Linda Wooldridge (Supervisor) & Laura Rivino (Supervisor)