Uhl et al. discovered that a subset of antigen-independent CD8+ memory T cells, virtual memory T cells (TVM; corresponding to a subset of CD8+ TEMRA cells in humans), played a critical role in regulating the average avidity of an endogenous immune response. IFNγ produced by TVM cells during priming and sensed in a paracrine manner as “signal 3” by other CD8+ T cells decreased the avidity of the primary effector T cell response, while increasing the avidity of the memory responses. IFNγ specifically promoted low-avidity T cell expansion, thereby overcoming the selective advantage of high-avidity T cells to enter the effector response, and reinforcing these high-avidity T cells to enter the memory pool.
Contributed by Ute Burkhardt
ABSTRACT: Effective responses to intracellular pathogens are characterized by T cell clones with a broad affinity range for their cognate peptide and diverse functional phenotypes. How T cell clones are selected throughout the response to retain a breadth of avidities remains unclear. Here, we demonstrate that direct sensing of the cytokine IFN-γ by CD8+ T cells coordinates avidity and differentiation during infection. IFN-γ promotes the expansion of low-avidity T cells, allowing them to overcome the selective advantage of high-avidity T cells, whilst reinforcing high-avidity T cell entry into the memory pool, thus reducing the average avidity of the primary response and increasing that of the memory response. IFN-γ in this context is mainly provided by virtual memory T cells, an antigen-inexperienced subset with memory features. Overall, we propose that IFN-γ and virtual memory T cells fulfil a critical immunoregulatory role by enabling the coordination of T cell avidity and fate.
Author Info: (1) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (2) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (3) The Kennedy Institute
Author Info: (1) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (2) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (3) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (4) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (5) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (6) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (7) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (8) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. (9) Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (10) Centre for Immuno-oncology, Nuffield Department of Medicine, University of Oxford, Oxford, UK. (11) The Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK. audrey.gerard@kennedy.ox.ac.uk.
