A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

McEntee, C. P.; Houston, S.; Finlay, C. M.; Rossi, S.; Liu, G.; Shaw, T. N.; Casulli, J.; Fife, M.; Smedley, C.; Griffith, T. S.; Pepper, M.; Hussell, T.; Hansbro, P. M.; Schwartz, J.-M.; Paidassi, H.; Travis, M. A.

doi:10.1101/2023.03.02.527395

bioRxiv · 10.1101/2023.03.02.527395

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

McEntee, C. P.·Houston, S.·Finlay, C. M.·Rossi, S.·Liu, G.·Shaw, T. N.·Casulli, J.·Fife, M.·Smedley, C.·Griffith, T. S.·Pepper, M.·Hussell, T.·Hansbro, P. M.·Schwartz, J.-M.·Paidassi, H.·Travis, M. A.

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Abstract

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

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McEntee, C. P., Houston, S., Finlay, C. M., Rossi, S., Liu, G., Shaw, T. N., Casulli, J., Fife, M., Smedley, C., Griffith, T. S., Pepper, M., Hussell, T., Hansbro, P. M., Schwartz, J.-M., Paidassi, H., Travis, M. A.. 2023-03-02. A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ. https://doi.org/10.1101/2023.03.02.527395

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