Modulation of CD4+Foxp3+ regulatory T cell responses in the lung during an acute heterologous LCMV infection in influenza‐immune mice

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In a mouse model of respiratory viral infection it has been previously shown that influenza (flu)‐immune compare to naïve mice infected with LCMV have enhanced viral load, severe lung pathology and an altered cytokine profile. We noted that more CD4+Foxp3+ regulatory T (Treg) cells were present in lungs of these flu‐immune mice compared to naïve or LCMV‐immune mice. Therefore, we questioned, whether a modulation in the normal balance of Treg and effector T cell responses might be contributing to these altered responses in flu‐immune mice infected with LCMV. We examined immune responses both at the site of the T cell activation (mLN) and the peripheral site of virus entry (lung). Flu‐immune mice had enhanced pro‐inflammatory cytokine and chemokine levels in the lungs and a higher frequency of Treg cells through out LCMV infection. In the mLN the Treg cell population in flu‐immune mice had altered kinetics compared to naïve mice infected with LCMV. Whereas Treg cells followed the same kinetics as CD4+ and CD8+ T cells in the mLN of acute LCMV‐infected mice (peak at day 3, decline by day 7), in flu‐immune mice the Treg cells persisted at higher levels, until day 9 after LCMV infection. The presence of increased Treg cells in flu‐immune lungs and the skewed Treg cell kinetics in subsequent heterologous LCMV respiratory infections may be contributing to increasing virus load and the enhanced lung pathology.