Multifunctional cytokine production marks influenza A virus-specific CD4 T cells with high expression of survival molecules

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Westerhof, Lotus M. and Noonan, Jonathan and Hargrave, Kerrie E. and Chimbayo, Elizabeth T. and Cheng, Zhiling and Purnell, Thomas and Jackson, Mark R. and Borcherding, Nicholas and MacLeod, Megan K.L. (2023) Multifunctional cytokine production marks influenza A virus-specific CD4 T cells with high expression of survival molecules. European Journal of Immunology, 53 (11). 2350559. ISSN 0014-2980 (https://doi.org/10.1002/eji.202350559)

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Abstract

Cytokine production by memory T cells is a key mechanism of T cell mediated protection. However, we have limited understanding of the persistence of cytokine producing T cells during memory cell maintenance and secondary responses. We interrogated antigen-specific CD4 T cells using a mouse influenza A virus infection model. Although CD4 T cells detected using MHCII tetramers declined in lymphoid and non-lymphoid organs, we found similar numbers of cytokine+ CD4 T cells at days 9 and 30 in the lymphoid organs. CD4 T cells with the capacity to produce cytokines expressed higher levels of pro-survival molecules, CD127 and Bcl2, than non-cytokine+ cells. Transcriptomic analysis revealed a heterogeneous population of memory CD4 T cells with three clusters of cytokine+ cells. These clusters match flow cytometry data and reveal an enhanced survival signature in cells capable of producing multiple cytokines. Following re-infection, multifunctional T cells expressed low levels of the proliferation marker, Ki67, whereas cells that only produce the anti-viral cytokine, interferon-γ, were more likely to be Ki67+. Despite this, multifunctional memory T cells formed a substantial fraction of the secondary memory pool. Together these data indicate that survival rather than proliferation may dictate which populations persist within the memory pool.

ORCID iDs

Westerhof, Lotus M., Noonan, Jonathan, Hargrave, Kerrie E. ORCID logoORCID: https://orcid.org/0000-0001-6015-4616, Chimbayo, Elizabeth T., Cheng, Zhiling, Purnell, Thomas, Jackson, Mark R., Borcherding, Nicholas and MacLeod, Megan K.L.;
CORE (COnnecting REpositories)