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      Long-term maintenance of lung resident memory T cells is mediated by persistent antigen


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          Tissue resident memory T cells (T RM) in the lungs are pivotal for protection against repeated infection with respiratory viruses. However, the gradual loss of these cells over time and the associated decline in clinical protection represent a serious limit in the development of efficient T-cell based vaccines against respiratory pathogens. Here, using an adenovirus expressing influenza nucleoprotein (AdNP) we show that CD8 T RM in the lungs can be maintained for at least one year post-vaccination. Our results reveal that lung T RM continued to proliferate in-situ 8 months after AdNP vaccination. Importantly, this required airway vaccination and antigen persistence in the lung, as non-respiratory routes of vaccination failed to support long-term lung T RM maintenance. Additionally, parabiosis experiments show that in AdNP vaccinated mice, the lung T RM pool is also sustained by continual replenishment from circulating memory CD8 T cells that differentiate into lung T RM, a phenomenon not observed in influenza infected parabiont partners. Concluding, these results demonstrates key requirements for long-lived cellular immunity to influenza virus, knowledge that could be utilized in future vaccine design.

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          Most cited references 48

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          Lung-resident memory CD8 T cells (TRM) are indispensable for optimal cross-protection against pulmonary virus infection.

          Previous studies have shown that some respiratory virus infections leave local populations of tissue TRM cells in the lungs which disappear as heterosubtypic immunity declines. The location of these TRM cells and their contribution to the protective CTL response have not been clearly defined. Here, fluorescence microscopy is used to show that some CD103(+) TRM cells remain embedded in the walls of the large airways long after pulmonary immunization but are absent from systemically primed mice. Viral clearance from the lungs of the locally immunized mice precedes the development of a robust Teff response in the lungs. Whereas large numbers of virus-specific CTLs collect around the bronchial tree during viral clearance, there is little involvement of the remaining lung tissue. Much larger numbers of TEM cells enter the lungs of the systemically immunized animals but do not prevent extensive viral replication or damage to the alveoli. Together, these experiments show that virus-specific antibodies and TRM cells are both required for optimal heterosubtypic immunity, whereas circulating memory CD8 T cells do not substantially alter the course of disease.
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            Coregulation of CD8+ T cell exhaustion during chronic viral infection by multiple inhibitory receptors

            T cell exhaustion often occurs during chronic infections and prevents optimal viral control. The molecular pathways involved in T cell exhaustion, however, remain poorly understood. We demonstrate that exhausted CD8+ T cells are subject to complex layers of negative regulation due to co-expression of multiple inhibitory receptors. Exhausted CD8+ T cells expressed up to 7 inhibitory receptors. Co-expression of multiple distinct inhibitory receptors correlated with greater T cell exhaustion and more severe infection. Regulation of T cell exhaustion by diverse inhibitory pathways was non-redundant since blockade of PD-1 and LAG-3 simultaneously in vivo synergistically improved T cell responses and reduced viral load. Thus, CD8+ T cell responses during chronic viral infections are regulated by complex patterns of co-expressed inhibitory receptors.
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              PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression.

              Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. The inhibitory receptor programmed death 1 (PD-1; also known as PDCD1), a negative regulator of activated T cells, is markedly upregulated on the surface of exhausted virus-specific CD8 T cells in mice. Blockade of this pathway using antibodies against the PD ligand 1 (PD-L1, also known as CD274) restores CD8 T-cell function and reduces viral load. To investigate the role of PD-1 in a chronic human viral infection, we examined PD-1 expression on human immunodeficiency virus (HIV)-specific CD8 T cells in 71 clade-C-infected people who were naive to anti-HIV treatments, using ten major histocompatibility complex (MHC) class I tetramers specific for frequently targeted epitopes. Here we report that PD-1 is significantly upregulated on these cells, and expression correlates with impaired HIV-specific CD8 T-cell function as well as predictors of disease progression: positively with plasma viral load and inversely with CD4 T-cell count. PD-1 expression on CD4 T cells likewise showed a positive correlation with viral load and an inverse correlation with CD4 T-cell count, and blockade of the pathway augmented HIV-specific CD4 and CD8 T-cell function. These data indicate that the immunoregulatory PD-1/PD-L1 pathway is operative during a persistent viral infection in humans, and define a reversible defect in HIV-specific T-cell function. Moreover, this pathway of reversible T-cell impairment provides a potential target for enhancing the function of exhausted T cells in chronic HIV infection.

                Author and article information

                Mucosal Immunol
                Mucosal Immunol
                Mucosal immunology
                6 June 2020
                09 June 2020
                January 2021
                10 January 2021
                : 14
                : 1
                : 92-99
                [1 ]Department of Immunology and Microbiology, University of Copenhagen, Copenhagen DK2200, Denmark
                [2 ]Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA 30322
                [3 ]Department of Immunology, Faculty of Medicine, Kindai University, Osaka-Sayama, Osaka 589-8511, Japan
                [4 ]Emory-UGA Center of Excellence for Influenza Research and Surveillance, Atlanta, GA, USA
                Author notes

                These first authors contributed equally to this work


                These last authors contributed equally to this work

                Author Contributions

                I.U. and E.K.C designed, performed, and analyzed most of the experiments with input from A.R.T, J.E.K, J.P.C.. A.S.S., S.L.H., J.L. carried out tetramer stainings and facs analysis. S.T. performed parabiosis experiments. A.N.W. desgined and performed immunofluorescence microscopy experiment and analysis. I.U. and E.K.C. wrote the manuscript and A.R.T, J.E.K, J.P.C. edited the manuscript.

                Corresponding authors: Jan P Christensen, jpc@ 123456sund.ku.dk and Jacob E Kohlmeier, jkohlmeier@ 123456emory.edu

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                tissue resident t cells, cd8 t cells, adenovirus, vaccines, antigen persistence


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