Invited Speaker Australian Society for Microbiology Annual Scientific Meeting 2022

Representing the team: selecting protein antigens for CD4+ T cell-mediated immunity against intracellular bacterial infection (83012)

Nancy Wang 1 , Ralf Schittenhelm 2 , Nichollas Scott 1 , Dianna Hocking 1 , Adrian Sememiuk 1 3 , Hugh Reid 2 , Jamie Rossjohn 2 , Meghanashree Shreenivas 1 , Anna Erazo 1 3 , Irmgard Forster 3 , Hanwei Cao 1 , Mark Davies 1 , Anthony Prucell 2 , Richard Strugnell 1
  1. Department of Microbiology and Immunology, The University of Melbourne, at Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
  2. Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia
  3. The Life and Medical Sciences Institute (LIMES), The University of Bonn, Bonn, Germany

CD4+ T cells effect protective immunity against many clinically important intracellular bacterial pathogens by recognising and responding to pathogen-derived peptide antigens.  Salmonella enterica serovar Typhimurium, a well-established model for probing CD4+ T cell immunity, has a proteome of >4,500 ORFs with >1,000 proteins expressed in the host, yet only a small subset of such protein antigens appear to elicit high-quality, protective CD4+ T cell responses in a phenomenon known as immunodominance.  The identity of these immunodominant antigens, and the mechanisms that govern their selection, remain largely unknown to date.  We have recently developed a global and unbiased approach for identifying Salmonella-derived peptide antigens that are naturally presented by MHC-II molecules for activating CD4+ T cells.  While we found CD4+ T cells against many of these peptide antigens in an infected host, the majority of infection-induced CD4+ T cells are focused on just a small subset of these newly identified antigens.  Interestingly, we observed that different antigens induced distinct types of cytokine responses in the host, suggesting a direct role for antigens in shaping the responses from, and the microenvironment of, activated CD4+ T cells.  These observations have enabled the discussion of some key questions, such as whether there are identifiable commonalities between immunodominant CD4+ T cell antigens, or whether antigen identity confers differential effector/memory CD4+ T cell development.  The ultimate goal is to provide a paradigm for antigen selection mechanisms that is broadly applicable to CD4+ T cell-mediated immunity against Salmonella and other complex pathogens.