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Resident help for fighting influenza: Memory T cells take up residence in the lung after respiratory virus infection to facilitate rapid and localized immune responses during reinfection. Two studies in this week's issue identify a population of CD4+ tissue–resident helper T cells in mice that are BCL6-dependent and support antiviral B cell responses within inducible bronchus-associated lymphoid tissue after influenza infection. Swarnalekha et al. used single-cell RNA sequencing of antigen-specific T cells across different tissues to characterize lung T resident helper cells and demonstrated that their development also requires B cells. Son et al. showed that T resident helper cells rely on Bhlhe40 for their survival and support protective CD8+ T cell responses by producing IL-21. These studies provide insight into the function of mucosal tissue-resident CD4+ T cells during viral infection. See related Research Article by Swarnalekha et al. and Focus by Schattgen et al. in this issue. Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21–dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses. [ABSTRACT FROM AUTHOR]

Role reversal for aged T cells: Age-related changes to the adaptive immune system are associated with impaired host response and increased morbidity and mortality after respiratory virus infection. Goplen et al. used a murine model of influenza virus infection to compare the function of lung tissue–resident memory T (TRM) cells in young and aged mice. Although TRM cells typically promote robust antiviral immunity, aged mice displayed increased accumulation of dysfunctional influenza-specific TRM cells that provided less protection against heterologous infection compared with TRM cells from young mice and facilitated pathological lung fibrosis. These results provide insight into how age and prior infection may affect T cell–mediated immunity to respiratory viruses such as influenza and SARS-CoV-2 and how these factors contribute to chronic lung pathology after viral pneumonia in older individuals. Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8+ tissue-resident memory T cells (TRM) in the respiratory tract of aged hosts. TRM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that TRM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, TRM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8+ TRM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated TRM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia. [ABSTRACT FROM AUTHOR]

Lower respiratory viral infections, such as influenza virus and severe acute respiratory syndrome coronavirus 2 infections, often cause severe viral pneumonia in aged individuals. Here, we report that influenza viral pneumonia leads to chronic nonresolving lung pathology and exacerbated accumulation of CD8 + tissue-resident memory T cells (T RM ) in the respiratory tract of aged hosts. T RM cell accumulation relies on elevated TGF-β present in aged tissues. Further, we show that T RM cells isolated from aged lungs lack a subpopulation characterized by expression of molecules involved in TCR signaling and effector function. Consequently, T RM cells from aged lungs were insufficient to provide heterologous protective immunity. The depletion of CD8 + T RM cells dampens persistent chronic lung inflammation and ameliorates tissue fibrosis in aged, but not young, animals. Collectively, our data demonstrate that age-associated T RM cell malfunction supports chronic lung inflammatory and fibrotic sequelae after viral pneumonia., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)