Seasonal outbreaks of Influenza A virus (IAV) infections repeatedly challenge the immune system, which is in charge of controlling viral replication and facilitating clearance and subsequently recovery. T cells, which are part of the adaptive immune system, provide a highly specific response towards IAV during the acute infection phase that supports viral clearance. For that, activated effector T cells migrate from the lung-draining lymph nodes (drLN) to the side of infection, where they induce cell death of infected cells. Besides effector function in the lung, the follicular T helper cell subset provides help to B cells in drLN thereby supporting plasma cell differentiation and production of neutralizing antibodies. Furthermore, memory T cells reside long term in the body and serve as protection against re-infections. Although the T cell response is crucial for virus control, it has to be tightly regulated as T cell induced immunopathology and collateral tissue damage is disadvantageous. The protein T cell activation inhibitor, mitochondrial (TCAIM) was previously found to interfere with effector T cell differentiation and function. Yet, TCAIM overexpressing T cells were able to respond to activating stimuli by entering the proliferation cycle and reduced cytokine production. Thus, within the scope of this work, the question was addressed, if the degree of T cell activation and differentiation in TCAIM overexpressing mice is sufficient to facilitate viral clearance and to support establishment of a protective memory T cell pool. Furthermore, no in vivo data are available for TCAIM deficient T cells, but previous in vitro work showed an advantage in T cell activation under sub-optimal stimulation conditions. This raises the question, whether viral control is improved in TCAIM deficient mice. The here presented data show an impaired lung infiltration of TCAIM overexpressing T cells upon IAV infection, which is linked to the failure to modulate CD44 and CD62L receptor expression and upregu-lation of genes involved in migration and effector T cell differentiation. As a functional consequence cytokine production was diminished and viral clearance delayed. Nevertheless, TCAIM overexpressing mice did recover from IAV infection and were able to respond to infection induced activation stimuli seen in undisturbed type I interferon (IFN) signalling and T cell expansion within drLN. Importantly, reduced T cell response at the side of infection prevented T cell induced immunopathology since TCAIM overexpressing mice only slightly lost weight. Surprisingly, although generation of lung homing effector and tissue resident memory T cells was impaired, neutralizing antibodies were formed which might serve as protection during re-infection. TCAIM deficient T cells were found to predominantly accumulate at the side of infection. Early upregulation of Ifng and genes involved in T cell activation however did not translate into increased IFN-γ production at the peak of infection and improved viral control. VI In conclusion, the data within this work highlight the impact of TCAIM on T cell migration and the prevention of T cell induced immunopathology thereby proposing a beneficial role during IAV infections.
