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Following a respiratory virus infection, CXCR3 hi CX3CR1 lo and CXCR3 lo CX3CR1 hi CD8 T cells localize to different compartments within the lung and play an important role in host resistance, but mechanisms governing their optimal generation are poorly defined. We serendipitously found that B cell-deficient (μMT -/- ) mice were highly resistant to lethal infection with a virulent poxvirus strain and that depletion of CD8 T cells rendered these mice susceptible to infection. B cells were not required for the expansion of virus-specific CD8 T cells, but a greater proportion of activated CD8 T cells acquired an effector-like CXCR3 lo CX3CR1 hi phenotype in the absence of B cells. After recovery from infection, CD8 T cells in μMT -/- mice contracted normally but failed to survive and seed the memory cell pool in both the lungs and spleen. These findings reveal a previously unappreciated role for B cells in regulating the balance between CD8 T cell-mediated resistance against respiratory viral infection and memory cell development. IMPORTANCE B cells play critical role in host resistance against many respiratory viral infections. However, the role of B cells beyond antibody-producing cells is less well defined. In this study, we made a surprising observation that mice lacking B cells were more resistant to respiratory infection with vaccinia virus than wild-type mice. This enhanced resistance was mediated by CD8 T cells because when we depleted CD8 T cells in B cell-deficient mice, these mice were unable to survive the infection. Interestingly, CD8 T cells in B cell-deficient mice were skewed more toward effector phenotype and less toward memory phenotype, which resulted in severely compromised memory CD8 T cell development. Thus, our study shows a novel role of B cells as regulators of CD8 T cell-mediated host resistance and memory CD8 T cell formation during respiratory viral infection., (Copyright © 2020 American Society for Microbiology.)

Respiratory infection with vaccinia virus (VacV) elicits robust CD8 + T cell responses that play an important role in host resistance. In the lung, VacV encounters multiple tissue-resident antigen-presenting cell (APC) populations, but which cell plays a dominant role in priming of virus-specific CD8 + effector T cell responses remains poorly defined. We used Batf3 -/- mice to investigate the impact of CD103 + and CD8α + dendritic cell (DC) deficiency on anti-VacV CD8 + T cell responses. We found that Batf3 -/- mice were more susceptible to VacV infection, exhibiting profound weight loss, which correlated with impaired accumulation of gamma interferon (IFN-γ)-producing CD8 + T cells in the lungs. This was largely due to defective priming since early in the response, antigen-specific CD8 + T cells in the draining lymph nodes of Batf3 -/- mice expressed significantly reduced levels of Ki67, CD25, and T-bet. These results underscore a specific role for Batf3-dependent DCs in regulating priming and expansion of effector CD8 + T cells necessary for host resistance against acute respiratory VacV infection. IMPORTANCE During respiratory infection with vaccinia virus (VacV), a member of Poxviridae family, CD8 + T cells play important role in resolving the primary infection. Effector CD8 + T cells clear the virus by accumulating in the infected lungs in large numbers and secreting molecules such as IFN-γ that kill virally infected cells. However, precise cell types that regulate the generation of effector CD8 + T cells in the lungs are not well defined. Dendritic cells (DCs) are a heterogeneous population of immune cells that are recognized as key initiators and regulators of T-cell-mediated immunity. In this study, we reveal that a specific subset of DCs that are dependent on the transcription factor Batf3 for their development regulate the magnitude of CD8 + T cell effector responses in the lungs, thereby providing protection during pulmonary VacV infection., (Copyright © 2018 American Society for Microbiology.)

The transition of effector T cells or memory precursors into distinct long-lived memory T cell subsets is not well understood. Although many molecules made by APCs can contribute to clonal expansion and effector cell differentiation, it is not clear if clonal contraction and memory development is passive or active. Using respiratory virus infection, we found that CD8 T cells that cannot express the TNF family molecule lymphotoxin-like, exhibits i nducible expression, competes with HSV g lycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes (LIGHT) are unimpaired in their initial response and clonally expand to form effector cell pools. Thereafter, LIGHT-deficient CD8 T cells undergo strikingly enhanced clonal contraction with resultant compromised accumulation of both circulating and tissue-resident memory cells. LIGHT expression at the peak of the effector response regulates the balance of several pro- and antiapoptotic genes, including Akt, and has a preferential impact on the development of the peripheral memory population. These results underscore the importance of LIGHT activity in programming memory CD8 T cell development, and suggest that CD8 effector T cells can dictate their own fate into becoming memory cells by expressing LIGHT., (Copyright © 2018 by The American Association of Immunologists, Inc.)

Phenotypically diverse memory CD8 + T cells are present in the lungs that either re-circulate or reside within the tissue. Understanding the key cellular interactions that regulate the generation and then persistence of these different subsets is of great interest. Recently, DNGR-1 + dendritic cell (DC) mediated priming was reported to control the generation of lung-resident but not circulating memory cells following respiratory viral infection. Here, we report an important role for Ly6C + inflammatory monocytes (IMs) in contributing to the persistence of memory CD8 + T cells but not their generation. Effector CD8 + T cells expanded and contracted normally in the absence of IMs, but the memory compartment declined significantly over time. Quite unexpectedly, this defect was confined to tissue resident and circulating CXCR3 hi CX3CR1 lo memory cells but not CXCR3 hi CX3CR1 int and CXCR3 lo CX3CR1 hi subsets. Thus, two developmentally distinct innate cells orchestrate the generation and persistence of memory T cell subsets following a respiratory virus infection. See also: News and Commentary by Lafouresse & Groom., (© 2018 Australasian Society for Immunology Inc.)

Mucosal immunity to reinfection with a highly virulent virus requires the accumulation and persistence of memory CD8 T cells at the site of primary infection. These cells may derive from memory precursor effector cells (MPECs), which are distinct from short-lived effector cells that provide acute protection but are often destined to die. Using respiratory virus infection, we show that herpes virus entry mediator (HVEM; TNFRSF14), a member of the TNF receptor superfamily, provides key signals for MPEC persistence. HVEM-deficient CD8 T cells expanded normally but were skewed away from MPECs with resultant poor development of circulating and lung-resident memory cells. HVEM was selectively expressed on MPECs whereas MPECs deficient in HVEM failed to survive in adoptive transfer recipients. As a consequence, HVEM-deficient recipients failed to afford protection against respiratory reinfection with influenza virus. HVEM therefore represents a critical signal for MPECs and development of protective mucosal CD8 T cell memory., (Copyright © 2017 by The American Association of Immunologists, Inc.)

How tissue-specific anatomical distribution and phenotypic specialization are linked to protective efficacy of memory T cells against reinfection is unclear. Here, we show that lung environmental cues program recently recruited central-like memory cells with migratory potentials for their tissue-specific functions during lethal respiratory virus infection. After entering the lung, some central-like cells retain their original CD27 hi CXCR3 hi phenotype, enabling them to localize near the infected bronchiolar epithelium and airway lumen to function as the first line of defense against pathogen encounter. Others, in response to local cytokine triggers, undergo a secondary program of differentiation that leads to the loss of CXCR3, migration arrest, and clustering within peribronchoarterial areas and in interalveolar septa. Here, the immune system adapts its response to prevent systemic viral dissemination and mortality. These results reveal the striking and unexpected spatial organization of central- versus effector-like memory cells within the lung and how cooperation between these two subsets contributes to host defense., (© 2016 Abboud et al.)

CD8 T cells are a key component of immunity to many viral infections. They achieve this through using an array of effector mechanisms, but precisely which component/s are required for protection against a respiratory orthopox virus infection remains unclear. Using a model of respiratory vaccinia virus infection in mice, we could specifically determine the relative contribution of perforin, TRAIL, and IFN-γ-mediated pathways in protection against virus induced morbidity and mortality. Unexpectedly, we observed that protection against death was mediated by IFN-γ without any involvement of the perforin or TRAIL-dependent pathways. IFN-γ mRNA and protein levels in the lung peaked between days 3 and 6 postinfection. This enhanced response coincided with the emergence of virus-specific CD8 T cells in the lung and the cessation of weight loss. Transfer experiments indicated that CD8 T cell-autonomous expression of IFN-γ restricts virus-induced lung pathology and dissemination to visceral tissues and is necessary for clearance of virus. Most significantly, we show that CD8 T cell-derived IFN-γ is sufficient to protect mice in the absence of CD4 and B-lymphocytes. Thus, our findings reveal a previously unappreciated mechanism by which effector CD8 T cells afford protection against a highly virulent respiratory orthopox virus infection., (Copyright © 2014 by The American Association of Immunologists, Inc.)