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Memory CD4+ T cells induce innate responses independently of pathogen

Abstract

Inflammation induced by recognition of pathogen-associated molecular patterns markedly affects subsequent adaptive responses. We asked whether the adaptive immune system can also affect the character and magnitude of innate inflammatory responses. We found that the response of memory, but not naive, CD4+ T cells enhances production of multiple innate inflammatory cytokines and chemokines (IICs) in the lung and that, during influenza infection, this leads to early control of virus. Memory CD4+ T cell–induced IICs and viral control require cognate antigen recognition and are optimal when memory cells are either T helper type 1 (TH1) or TH17 polarized but are independent of interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) production and do not require activation of conserved pathogen recognition pathways. This represents a previously undescribed mechanism by which memory CD4+ T cells induce an early innate response that enhances immune protection against pathogens.

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Figure 1: Memory CD4+ T cells induce an acute increase in IICs upon influenza infection.
Figure 2: Role of IFN-γ, TNF-α and CCL3 in IIC upregulation by memory CD4+ T cells.
Figure 3: TH1- or TH17-polarization is required for enhanced IIC response and viral control.
Figure 4: Recognition of antigen in the lung is sufficient for IIC upregulation.
Figure 5: Cognate recognition of antigen on MHC class II–expressing CD11c+ cells is sufficient to induce IIC upregulation.
Figure 6: Memory CD4+ T cells induce IIC responses independently of PAMP recognition.

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Acknowledgements

This work was supported by the US National Institutes of Health (P01AI04630 to and P01AI04566 to S.L.S.), the US Department of Defense (HR#3222) and the Trudeau Institute. We thank J. Kohlmeier and D. Woodland (Trudeau Institute) for Ccr5−/− and Ifnar2−/− mice and M. Mohrs (Trudeau Institute) for C57BL/6-Tg (IFN-γ–EYFP) mice. Influenza A/Philippines was obtained from S. Epstein (CBER FDA), and engineered virus A/PR8-OVAII was obtained from P. Doherty (University of Melbourne). LPS-free whole OVA protein was a generous gift from T. Moran (Mount Sinai School of Medicine).

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T.M.S. and K.K.M. contributed equally to the design, processing, collection and analysis of data and, together with S.L.S., wrote the paper. S.L.S. and R.W.D. contributed to study design. J.P.D., C.W., Y.K., J.D.C. and G.H. processed and collected data. All authors discussed results and commented on the manuscript.

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Correspondence to Tara M Strutt.

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Strutt, T., McKinstry, K., Dibble, J. et al. Memory CD4+ T cells induce innate responses independently of pathogen. Nat Med 16, 558–564 (2010). https://doi.org/10.1038/nm.2142

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