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Staphylococcus aureus bacteremia causes significant morbidity and mortality. Treatment of staphylococcal infections is hindered by widespread antibiotic resistance, and attempts to develop an S. aureus vaccine have failed. Improved S. aureus treatment and infection prevention options require a deeper understanding of the correlates of protective immunity. CD4+ T cells have been identified as key orchestrators in the defense against S. aureus, but uncertainties persist regarding the subset, polarity, and breadth of the memory CD4+ T-cell pool required for protection. Here, using a mouse model of systemic S. aureus infection, we discovered that the breadth of bacterium-specific memory CD4+ T-cell pool is a critical factor for protective immunity against invasive S. aureus infections. Seeding mice with a monoclonal bacterium-specific circulating memory CD4+ T-cell population failed to protect against systemic S. aureus infection; however, the introduction of a polyclonal and polyfunctional memory CD4+ T-cell pool significantly reduced the bacterial burden. Our findings support the development of a multi-epitope T-cell-based S. aureus vaccine, as a strategy to mitigate the severity of S. aureus bacteremia. [ABSTRACT FROM AUTHOR]

Influenza B viruses (IBVs) cause substantive morbidity and mortality, and yet immunity towards IBVs remains understudied. CD8+ T-cells provide broadly cross-reactive immunity and alleviate disease severity by recognizing conserved epitopes. Despite the IBV burden, only 18 IBV-specific T-cell epitopes restricted by 5 HLAs have been identified currently. A broader array of conserved IBV T-cell epitopes is needed to develop effective cross-reactive T-cell based IBV vaccines. Here we identify 9 highly conserved IBV CD8+ T-cell epitopes restricted to HLA-B*07:02, HLA-B*08:01 and HLA-B*35:01. Memory IBVspecific tetramer+ CD8+ T-cells are present within blood and tissues. Frequencies of IBV-specific CD8+ T-cells decline with age, but maintain a central memory phenotype. HLA-B*07:02 and HLA-B*08:01-restricted NP30-38 epitopespecific T-cells have distinct T-cell receptor repertoires. We provide structural basis for the IBV HLA-B*07:02-restricted NS1196-206 (11-mer) and HLA-B*07:02- restricted NP30-38 epitope presentation. Our study increases the number of IBV CD8+ T-cell epitopes, and defines IBV-specific CD8+ T-cells at cellular and molecular levels, across tissues and age. [ABSTRACT FROM AUTHOR]

The human lung harbors a large population of resident memory T cells (Trm cells). These cells are perfectly positioned to mediate rapid protection against respiratory pathogens such as influenza virus, a highly contagious respiratory pathogen that continues to be a major public health burden. Animal models show that influenza-specific lung [CD8.sup.+] Trm cells are indispensable for crossprotection against pulmonary infection with different influenza virus strains. However, it is not known whether influenza-specific [CD8.sup.+] Trm cells present within the human lung have the same critical role in modulating the course of the disease. Here, we showed that human lung contains a population of [CD8.sup.+] Trm cells that are highly proliferative and have polyfunctional progeny. We observed that different influenza virus-specific [CD8.sup.+] T cell specificities differentiated into Trm cells with varying efficiencies and that the size of the influenza-specific [CD8.sup.+] T cell population persisting in the lung directly correlated with the efficiency of differentiation into Trm cells. To our knowledge, we provide the first ex vivo dissection of paired T cell receptor (TCR) repertoires of human influenza-specific [CD8.sup.+] Trm cells. Our data reveal diverse TCR profiles within the human lung Trm cells and a high degree of clonal sharing with other [CD8.sup.+] T cell populations, a feature important for effective T cell function and protection against the generation of viral-escape mutants., Introduction Influenza A viruses cause substantial morbidity and mortality worldwide. Vaccination is considered to be the best way to prevent human influenza disease. Current antibody-based vaccines are highly effective in [...]

Prior infection can generate protective immunity against subsequent infection, although the efficacy of such immunity can vary considerably. Live-attenuated vaccines (LAVs) are one of the most effective methods for mimicking this natural process, and analysis of their efficacy has proven instrumental in the identification of protective immune mechanisms. Here, we address the question of what makes a LAV efficacious by characterising immune responses to a LAV, termed TAS2010, which is highly protective (80–90%) against lethal murine salmonellosis, in comparison with a moderately protective (40–50%) LAV, BRD509. Mice vaccinated with TAS2010 developed immunity systemically and were protected against gut-associated virulent infection in a CD4+ T cell-dependent manner. TAS2010-vaccinated mice showed increased activation of Th1 responses compared with their BRD509-vaccinated counterparts, leading to increased Th1 memory populations in both lymphoid and non-lymphoid organs. The optimal development of Th1-driven immunity was closely correlated with the activation of CD11b+Ly6GnegLy6Chi inflammatory monocytes (IMs), the activation of which can be modulated proportionally by bacterial load in vivo. Upon vaccination with the LAV, IMs expressed T cell chemoattractant CXCL9 that attracted CD4+ T cells to the foci of infection, where IMs also served as a potent source of antigen presentation and Th1-promoting cytokine IL-12. The expression of MHC-II in IMs was rapidly upregulated following vaccination and then maintained at an elevated level in immune mice, suggesting IMs may have a role in sustained antigen stimulation. Our findings present a longitudinal analysis of CD4+ T cell development post-vaccination with an intracellular bacterial LAV, and highlight the benefit of inflammation in the development of Th1 immunity. Future studies focusing on the induction of IMs may reveal key strategies for improving vaccine-induced T cell immunity. Author summary: Salmonella enterica infections exemplify the immunological challenges posed by intracellular bacterial pathogens, for which there are often limited or no effective vaccines and antimicrobial resistance is rapidly on the rise. A common signature among these infections is a strong dependence on CD4+ T cell responses for host immunity, although how such responses can be effectively induced in a vaccine setting remains a key challenge. Using two live-attenuated vaccines that offer distinct levels of protection against lethal salmonellosis in a murine model, we investigated what properties of vaccine-induced immune responses can be targeted for improving vaccine efficacy. Our data show that the longevity of activated CD4+ T cells in lymphoid and non-lymphoid organs is closely linked with vaccine efficacy. At the cellular level, we have shown that CD11b+Ly6GnegLy6Chi inflammatory monocytes play an important role in stimulating antigen-specific CD4+ T cells through antigen presentation mechanisms, as well as the production of CXCL9 and IL-12. Since our data suggest that acute inflammation is beneficial for optimising vaccine-induced T cell immunity, considerations should be given to preserving the targets of inflammatory signalling pathways as a means for improving vaccine efficacy in future development. [ABSTRACT FROM AUTHOR]

Older individuals exhibit a diminished ability to respond to and clear respiratory pathogens and, as such, experience a higher rate of lung infections with a higher mortality rate. It is unclear why respiratory pathogens impact older people disproportionately. Using human lung tissue from donors aged 22–68 years, we assessed how the immune cell landscape in lungs changes throughout life and investigated how these immune cells respond following in vitro exposure to influenza virus and SARS‐CoV‐2, two clinically relevant respiratory viruses. While the frequency of most immune cell subsets profiled in the human lung remained stable with age, memory CD8+ T cells declined, with the tissue‐resident memory (Trm) CD8+ T‐cell subset being most susceptible to age‐associated attrition. Infection of lung tissue with influenza virus resulted in an age‐associated attenuation in the antiviral immune response, with aged donors producing less type I interferon (IFN), GM‐CSF and IFNγ, the latter correlated with a reduction of IFNγ‐producing memory CD8+ T cells. In contrast, irrespective of donor age, exposure of human lung cells to SARS‐CoV‐2, a pathogen for which all donors were immunologically naïve, did not trigger activation of local immune cells and did not result in the induction of an early IFN response. Our findings show that the attrition of tissue‐bound pathogen‐specific Trm in the lung that occurs with advanced age, or their absence in immunologically naïve individuals, results in a diminished early antiviral immune response which creates a window of opportunity for respiratory pathogens to gain a greater foothold. [ABSTRACT FROM AUTHOR]

An improved understanding of human T cell-mediated immunity in COVID-19 is important for optimizing therapeutic and vaccine strategies. Experience with influenza shows that infection primes CD8+ T cell memory to peptides presented by common HLA types like HLA-A2, which enhances recovery and diminishes clinical severity upon reinfection. Stimulating peripheral blood mononuclear cells from COVID-19 convalescent patients with overlapping peptides from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to the clonal expansion of SARS-CoV-2−specific CD8+ and CD4+ T cells in vitro, with CD4+ T cells being robust. We identified two HLAA* 02:01-restricted SARS-CoV-2-specfic CD8+ T cell epitopes, A2/ S269–277 and A2/Orf1ab3183–3191. Using peptide−HLA tetramer enrichment, direct ex vivo assessment of A2/S269 +CD8+ and A2/ Orf1ab3183 +CD8+ populations indicated that A2/S269 +CD8+ T cellswere detected at comparable frequencies (∼1.3 × 10−5) in acute and convalescent HLA-A*02:01+ patients. These frequencies were higher than those found in uninfected HLA-A*02:01+ donors (∼2.5 × 10−6), but low when compared to frequencies for influenza-specific (A2/M158) and Epstein–Barr virus (EBV)-specific (A2/BMLF1280) (∼1.38 × 10−4) populations. Phenotyping A2/S269 +CD8+ T cells from COVID-19 convalescents ex vivo showed that A2/S269 +CD8+ T cells were predominantly negative for CD38, HLA-DR, PD-1, and CD71 activation markers, although the majority of total CD8+ T cells expressed granzymes and/or perforin. Furthermore, the bias toward naïve, stem cell memory and central memory A2/S269 +CD8+ T cells rather than effector memory populations suggests that SARS-CoV-2 infection may be compromising CD8+ T cell activation. Priming with appropriate vaccines may thus be beneficial for optimizing CD8+ T cell immunity in COVID-19. [ABSTRACT FROM AUTHOR]