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Abstract: 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 CXCR3hiCX3CR1lo memory cells but not CXCR3hiCX3CR1int and CXCR3loCX3CR1hi 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 [ABSTRACT FROM AUTHOR]

Attenuated vaccinia virus (VACV) vectors are considered prime vaccine candidates for use in immunotherapy of infectious disease. In spite of this, recent data show that the level of attenuation may hamper the efficient generation of protective CD8 T cells. This suggests that additional adjuvant-like activities may need to be combined with attenuated VACV for optimal vaccination. Stimulatory reagents to theTNFR family molecule 4-1BB (CD137) may represent such an adjuvant for vaccination. Previous murine studies have found that 4-1BB can participate in optimal priming of effector and memory CD8 T cells in response to several virus infections, and concordantly direct stimulation of 4-1BB with agonist reagents effectively boosts the CD8 T cell response against those viruses. In contrast, we recently reported that 4-1BB plays no role in the response to a virulent strain of VACV, questioning whether agonists of 4-1BB will be useful adjuvants for vaccination withVACV vectors. Here we show that agonist anti-4-1BB strongly enhanced the primary viral-specific effector CD8 T cell response during infection with live virulent VACV and attenuated VACV, and during immunization with VACV peptides given in IFA. However, accumulation of memory CD8 T cells was enhanced only following infection with virulentVACV or with peptide vaccination, but not with attenuated VACV, correlating in part with more transient expression of 4-1BB on CD8 T cells with attenuated virus. Our data therefore suggest that 4-1BB may be a promising candidate for targeting as an adjuvant for short-term enhancement of CD8T cell responses with VACV vaccine strategies, but additional receptors may need to be engaged with 4-1BB to allow long-term CD8T cell immunity with attenuated VACV vectors [ABSTRACT FROM AUTHOR]

Summary: The human respiratory tract is an entry point for over 200 known viruses that collectively contribute to millions of annual deaths worldwide. Consequently, the World Health Organization has designated respiratory viral infections as a priority for vaccine development. Despite enormous advances in understanding the attributes of a protective mucosal antiviral immune response, current vaccines continue to fail in effectively generating long-lived protective CD8+ T-cell immunity. To date, the majority of licensed human vaccines afford protection against infectious pathogens through the generation of specific immunoglobulin responses. In recent years, the selective manipulation of specific costimulatory pathways, which are critical in regulating T cell-mediated immune responses, has generated increasing interest. Impressive results in animal models have shown that the tumor necrosis factor receptor (TNFR) family member OX40 (CD134) and its binding partner OX40L (CD252) are key costimulatory molecules involved in the generation of protective CD8+ T-cell responses at mucosal surfaces, such as the lung. In this review, we highlight these new findings with a particular emphasis on their potential as immunological adjuvants to enhance poxvirus-based CD8+ T-cell vaccines. [ABSTRACT FROM AUTHOR]

Following a respiratory virus infection, CXCR3hiCX3CR1lo and CXCR3loCX3CR1hi 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 (MT-/-) mice were highly resistant to lethal infection with a virulent poxvirus strain and depletion of CD8 T cells rendered these mice susceptible to infection. B cells were not required for the expansion of virus30 specific CD8 T cells but a greater proportion of activated CD8 T cells acquired an effector-like CXCR3loCX3CR1hi phenotype in absence of B cells. After recovery from infection, CD8 T cells in MT-/- mice contracted normally but failed to survive and seed the memory 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 development. [ABSTRACT FROM AUTHOR]