T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming


Although clearance of many intracellular pathogens requires T-bet-dependent CD4 T cell programming, the extent to which T-bet is needed to direct protective CD4 responses against influenza is not known. Here, we characterize wild-type and T-bet-deficient CD4 cells during murine influenza infection. Surprisingly, although T-bet expression has broad impacts on cytokine production by virus-specific CD4 cells, the protective efficacy of T-bet-deficient effector cells is only marginally reduced. This reduction is due to lower CXCR3 expression, leading to suboptimal accumulation of activated T-bet-deficient cells in the infected lung. However, T-bet-deficient cells outcompete wild-type cells to form lung-resident and circulating memory populations following viral clearance, and primed T-bet-deficient mice efficiently clear supralethal heterosubtypic influenza challenges even when depleted of CD8 T cells. These results are relevant to the identification of more incisive correlates of protective T cells and for vaccines that aim to induce durable cellular immunity against influenza.

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We thank the NIH Tetramer Core Facility for providing the NP311–235 tetramer and control reagents. We thank the University of Central Florida’s Vivarium staff for providing excellent care for the animals in this study. We thank Dr. Priyadharshini Devarajan for helpful discussions. This work was supported by American Heart Association grant 14SDG18600020 (to K.K.M.), National Institutes of Health Grant AI117457 (to T.M.S.) and by funds provided by the University of Central Florida.

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K.D. and C.F. performed all experiments. K.D. and K.K.M. analyzed data and wrote the manuscript. S.S. performed blinded analysis of histopathology. T.M.S. provided key reagents, reviewed and critiqued the manuscript and figures, and contributed to interpretation of the findings.

Correspondence to K. Kai McKinstry.

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Dhume, K., Finn, C.M., Strutt, T.M. et al. T-bet optimizes CD4 T-cell responses against influenza through CXCR3-dependent lung trafficking but not functional programming. Mucosal Immunol 12, 1220–1230 (2019). https://doi.org/10.1038/s41385-019-0183-z

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