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.