Explore the vast range of titles available.

Despite the fundamental role of vaccines in the decline of infant mortality, parents may decide to decline vaccination for their own children. Many factors may influence this decision, such as the belief that the infant immune system is weakened by vaccines, and concerns have been raised about the number of vaccines and the early age at which they are administered. Studies focused on the infant immune system and its reaction to immunizations, summarized in this review, show that vaccines can overcome those suboptimal features of infant immune system that render them more at risk of infections and of their severe manifestations. In addition, many vaccines have been shown to improve heterologous innate and adaptive immunity resulting in lower mortality rates for fully vaccinated children. Thus, multiple vaccinations are necessary and not dangerous, as infants can respond to several antigens as well as when responding to single stimuli. Current immunization schedules have been developed and tested to avoid vaccine interference, improve benefits and reduce side effects compared to single administrations. The infant immune system is therefore capable, early after birth, of managing several antigenic challenges and exploits them to prompt its development.

People living with HIV-1 (PLWH) are a population at higher risk for communicable disease and therefore a target group for vaccination. Owing to the success of anti-retroviral therapy, PLWH live longer, but face new challenges related to ageing, which add to their underlying immunodeficiencies. We review here the immune dysregulations occurring with chronic HIV-1 infection and ageing in the era of antiretroviral therapy, focusing on cellular mechanisms that can explain the lower immune response to most vaccines in older treated PLWH, and we discuss potential developments to improve vaccination strategies in this specific population.

Cytotoxic CD8 T-cells are key players of the immune responses against viruses. During the priming of a CD8 T-cell response, the activation of a naïve T-cell by a professional antigen presenting cell (APC) involves the induction of various intracellular and metabolic pathways. The modulation of these pathways at the level of APCs or T-cells offers great potential to enhance the induction of robust effector cells and the generation of long-lived memory cells. On the one hand, signaling through pathogen recognition receptors (PRRs) expressed by APCs can greatly influence T-cell priming, and the potential of several PRR ligands as adjuvants are being studied. On the other hand, the engagement of several metabolic processes, at play in APCs and T-cells upon stimulation, implies that modulating cellular metabolism can impact on priming efficacy. Here, we review recent efforts to understand the interplay between PRR mediated signaling and metabolic pathway modulation in this context, through three examples: interplay between TLR4 and fatty acid metabolism, between TLR9 and IDO, and between STING and autophagy. These initial works highlight the potential for harnessing the induction of antiviral CD8 T-cell responses using synergistic modulation of metabolic and PRR pathways.

Although vaccine development has primarily focused on inducing neutralizing antibodies, increasing evidence supports an important role of CD8+ T cell responses in vaccine effectiveness. Routine assays, which are mainly based on antibody titers, may therefore not accurately reflect the full immune response elicited by vaccination. Assessing antigen-specific T cell responses upon vaccination poses several challenges. A common issue in studying T cells specific to a vaccine antigen is their low frequency in circulation, which can limit their ex vivo analysis. Moreover, the use of human cell-based models is crucial for studying and optimizing the induction of T cell responses to design effective vaccines. We developed an innovative in vitro approach of human CD8+ T cell priming, based on the rapid mobilization of dendritic cells (DCs) directly from unfractionated peripheral blood mononuclear cells (PBMCs). This simple and original method allows for side-by-side comparisons of multiple test parameters in a standardized system, providing both quantitative and qualitative readouts of primed antigen-specific CD8+ T cells. Here, we discuss the genesis of this approach and its versatile applications, including monitoring antigen-specific T cell responses, evaluating an individual’s T cell priming capacity, and conducting preclinical studies on potential adjuvants and vaccine candidates.

Understanding the factors that delineate the efficacy of T cell responses towards pathogens is crucial for our ability to develop potent therapies against infectious diseases. Multidimensional evaluation of T cell functionality at the single-cell level enables exhaustive analysis of combinatorial functional properties, hence polyfunctionality. We have recently invented an algorithm that quantifies polyfunctionality, the Polyfunctionality Index (Larsen et al. PLoS One 2012). Here we demonstrate that quantitative assessment of T cell polyfunctionality correlates with T cell efficacy measured as the capacity to kill target cells in vitro and control infection in vivo. We employed the polyfunctionality index on two datasets selected for their unique ability to evaluate the polyfunctional imprint on T cell efficacy. 1) HIV-specific CD8+ T cells and 2) Leishmania major-specific CD4+ T cells were analysed for their capacity to secrete multiple effector molecules, kill target cells and control infection. Briefly, employing the Polyfunctionality Index algorithm we determined the parameter estimates resulting in optimal correlation between T cell polyfunctionality and T cell efficacy. T cell polyfunctionality is correlated with T cell efficacy measured as 1) target killing (r=0.807, P<0.0001) and 2) lesion size upon challenge with Leishmania major (r=-0.50, P=0.004). Contrary to an approach relying on the Polyfunctionality Index algorithm, quantitative evaluation of T cell polyfunctionality traditionally ignores the gradual contribution of more or less polyfunctional T cells. Indeed, comparing both approaches we show that optimal description of T cell efficacy is obtained when gradually integrating all levels of polyfunctionality in accordance with the Polyfunctionality Index. Our study presents a generalizable methodology to objectively evaluate the impact of polyfunctionality on T cell efficacy. We show that T cell polyfunctionality is a superior correlate of T cell efficacy both in vitro and in vivo as compared with response size. Therefore, future immunotherapies should aim to increase T cell polyfunctionality.

Toll-like receptor 9 (TLR9) agonists have gained traction in recent years as potential adjuvants for the induction of adaptive immune responses. It has nonetheless remained unclear to what extent such ligands can facilitate the priming events that generate antigen-specific effector and/or memory CD8 + T-cell populations. We used an established in vitro model to prime naive precursors from human peripheral blood mononuclear cells in the presence of various adjuvants, including CpG ODN 2006, a synthetic oligonucleotide TLR9 ligand (TLR9L). Unexpectedly, we found that TLR9L induced a suboptimal inflammatory milieu and promoted the antigen-driven expansion and functional maturation of naive CD8 + T cells ineffectively compared with either ssRNA40 or 2′3′-cGAMP, which activate other pattern recognition receptors (PRRs). TLR9L also inhibited the priming efficacy of 2′3′-cGAMP. Collectively, these results suggest that TLR9L is unlikely to be a good candidate for the optimal induction of de novo CD8 + T-cell responses, in contrast to adjuvants that operate via discrete PRRs.

Functional evaluation of naturally occurring or vaccination-induced T cell responses in mice, men and monkeys has in recent years advanced from single-parameter (e.g. IFN-γ-secretion) to much more complex multidimensional measurements. Co-secretion of multiple functional molecules (such as cytokines and chemokines) at the single-cell level is now measurable due primarily to major advances in multiparametric flow cytometry. The very extensive and complex datasets generated by this technology raise the demand for proper analytical tools that enable the analysis of combinatorial functional properties of T cells, hence polyfunctionality. Presently, multidimensional functional measures are analysed either by evaluating all combinations of parameters individually or by summing frequencies of combinations that include the same number of simultaneous functions. Often these evaluations are visualized as pie charts. Whereas pie charts effectively represent and compare average polyfunctionality profiles of particular T cell subsets or patient groups, they do not document the degree or variation of polyfunctionality within a group nor does it allow more sophisticated statistical analysis. Here we propose a novel polyfunctionality index that numerically evaluates the degree and variation of polyfuntionality, and enable comparative and correlative parametric and non-parametric statistical tests. Moreover, it allows the usage of more advanced statistical approaches, such as cluster analysis. We believe that the polyfunctionality index will render polyfunctionality an appropriate end-point measure in future studies of T cell responsiveness.

Characterization of the intracellular biochemical processes that regulate the generation and maintenance of effector and memory CD8 T-cells from naïve precursors is essential for our understanding of adaptive immune responses and the development of immunotherapies. However, the metabolic determinants of antigen-driven activation and differentiation remain poorly defined, especially in humans. We used a variety of different approaches, including gene expression profiling and measurements of nutrient flux, to characterize the basal and activation-induced energetic requirements of naïve and phenotypically-defined subsets of human memory CD8 T-cells. Profound metabolic differences were apparent as a function of differentiation status, both at rest and in response to stimulation via the T cell receptor (TCR). Of particular note, resting naïve CD8 T cells were largely quiescent, but rapidly upregulated diverse energetic pathways after ligation of surface-expressed TCRs. Moreover, autophagy and the mechanistic target of rapamycin (mTOR)-dependent glycolytic pathway were identified as critical mediators of antigen-driven priming in the naïve CD8 T cell pool, the efficiency of which was dampened by the presence of neutral lipids and fatty acids. These observations provide a metabolic roadmap of the CD8 T-cell compartment in humans and reveal potentially selective targets for novel immunotherapies.

Systemic Lupus Erythematosus (SLE) pathology has long been associated with an increased Epstein-Barr Virus (EBV) seropositivity, viremia and cross-reactive serum antibodies specific for both virus and self. It has therefore been postulated that EBV triggers SLE immunopathology, although the mechanism remains elusive. Here, we investigate whether frequent peaks of EBV viral load in SLE patients are a consequence of dysfunctional anti-EBV CD8+ T cell responses. Both inactive and active SLE patients (n = 76 and 42, respectively), have significantly elevated EBV viral loads (P = 0.003 and 0.002, respectively) compared to age- and sex-matched healthy controls (n = 29). Interestingly, less EBV-specific CD8+ T cells are able to secrete multiple cytokines (IFN-γ, TNF-α, IL-2 and MIP-1β) in inactive and active SLE patients compared to controls (P = 0.0003 and 0.0084, respectively). Moreover, EBV-specific CD8+ T cells are also less cytotoxic in SLE patients than in controls (CD107a expression: P = 0.0009, Granzyme B release: P = 0.0001). Importantly, cytomegalovirus (CMV)-specific responses were not found significantly altered in SLE patients. Furthermore, we demonstrate that EBV-specific CD8+ T cell impairment is a consequence of their Programmed Death 1 (PD-1) receptor up-regulation, as blocking this pathway reverses the dysfunctional phenotype. Finally, prospective monitoring of lupus patients revealed that disease flares precede EBV reactivation. In conclusion, EBV-specific CD8+ T cell responses in SLE patients are functionally impaired, but EBV reactivation appears to be an aggravating consequence rather than a cause of SLE immunopathology. We therefore propose that autoimmune B cell activation during flares drives frequent EBV reactivation, which contributes in a vicious circle to the perpetuation of immune activation in SLE patients.

Ageing is accompanied by a decline in immune function, associated with susceptibility to infections and malignancies, and reduced vaccine efficacy. These immunological changes, affect multiple components of the immune system, particularly T lymphocytes, which exhibit altered subset distributions and accumulate senescent features. CD57, a surface glycoprotein expressed on T cells, has emerged as a potential marker of terminal differentiation and senescence used for immunomonitoring in infection or cancer contexts. However, the use of CD57 as a marker of T cell senescence remains unclear. To investigate this, we analyzed CD57 expression on CD8 + and CD4 + T cells in healthy donors from two independent cohorts, considering cellular differentiation, age, cytomegalovirus status, and other senescence markers. Our findings reinforce the association between CD57 expression, T cell differentiation, and CMV seropositivity, but not with chronological age. Although CD57 is associated with altered proliferation and survival in all T cell differentiation subsets, it does not fully align with a senescent phenotype. Therefore, we propose that CD57 may be better appreciated as a marker of immunological age. Moreover, the interpretation of CD57 expression must account for CMV serostatus to avoid misleading conclusions, especially in oncology and ageing research.