T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections

Santiago-Carvalho, I.; Almeida-Santos, G.; Macedo, B. G.; Bomfim, C. C. B.; Almeida, F. M.; Cione, M. V. P.; Vardam-Kaur, T.; Masuda, M.; van Dijk, S.; Melo, B. M.; Nascimento, R. S. d.; Souza, R. d. C.; Peixoto-Rangel, A. L.; Coutinho-Silva, R.; Hirata, M. H.; Alves-Filho, J. C.; Alvarez, J. M.; Lassounskaia, E.; da Silva, H. B.; Lima, M. R. D.

doi:10.1101/2022.09.19.508603

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bioRxiv · 10.1101/2022.09.19.508603

T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections

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Abstract

CD4+ T cells are key components of the immune response during lung infections and can mediate protection against tuberculosis (TB) or influenza. However, CD4+ T cells can also promote lung pathology during these infections, making it unclear how these cells control such discrepant effects. Using mouse models of hypervirulent TB and influenza, we observed that exaggerated accumulation of parenchymal CD4+ T cells promotes lung damage. Low numbers of lung CD4+ T cells, in contrast, are sufficient to protect against hypervirulent TB. In both situations, lung CD4+ T cell accumulation is mediated by CD4+ T cell-specific expression of the extracellular ATP (eATP) receptor P2RX7. P2RX7 upregulation in lung CD4+ T cells promotes expression of the chemokine receptor CXCR3 and favors in situ proliferation. Our findings suggest that direct sensing of lung eATP by CD4+ T cells is critical to induce tissue CD4+ T cell accumulation and pathology during lung infections. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=168 SRC="FIGDIR/small/508603v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@a4cdaborg.highwire.dtl.DTLVardef@1ba95e1org.highwire.dtl.DTLVardef@c60984org.highwire.dtl.DTLVardef@19ac0af_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Santiago-Carvalho, I., Almeida-Santos, G., Macedo, B. G., Bomfim, C. C. B., Almeida, F. M., Cione, M. V. P., Vardam-Kaur, T., Masuda, M., van Dijk, S., Melo, B. M., Nascimento, R. S. d., Souza, R. d. C., Peixoto-Rangel, A. L., Coutinho-Silva, R., Hirata, M. H., Alves-Filho, J. C., Alvarez, J. M., Lassounskaia, E., da Silva, H. B., Lima, M. R. D.. 2022-09-19. T cell-specific P2RX7 favors lung parenchymal CD4+ T cell accumulation in response to severe lung infections. https://doi.org/10.1101/2022.09.19.508603

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