Interferon-γ couples CD8+ T cell avidity and differentiation during infection

Lion F. K. Uhl, Han Cai, Sophia L. Oram, Jagdish N. Mahale, Andrew J. MacLean, Julie M. Mazet, Theo Piccirilli, Alexander J. He, Doreen Lau, Tim Elliott and Audrey Gerard ()
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Lion F. K. Uhl: University of Oxford
Han Cai: University of Oxford
Sophia L. Oram: University of Oxford
Jagdish N. Mahale: University of Oxford
Andrew J. MacLean: University of Oxford
Julie M. Mazet: University of Oxford
Theo Piccirilli: University of Oxford
Alexander J. He: University of Oxford
Doreen Lau: University of Oxford
Tim Elliott: University of Oxford
Audrey Gerard: University of Oxford

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42455-4

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