Elimination of the latent HIV reservoir remains a major barrier to achieving an HIV cure. In this review, we discuss the cytolytic nature of human gamma delta T cells and highlight the emerging ...evidence that they can target and eliminate HIV-infected T cells. Based on observations from human clinical trials assessing gamma delta immunotherapy in oncology, we suggest key questions and research priorities for the study of these unique T cells in HIV cure research.
Translating viral vaccines into immunity Juno, Jennifer A; O'Connor, Shelby L
Science (American Association for the Advancement of Science),
01/2021, Volume:
371, Issue:
6528
Journal Article
Influenza virus infection is a global public health threat. Current seasonal influenza vaccines are efficacious only when vaccine strains are matched with circulating strains. There is a critical ...need for developing "universal" vaccines that protect against all influenza viruses. HA stem is a promising target for developing broad-spectrum influenza vaccines due to its relatively conserved feature. However, HA stem is weakly immunogenic when administered alone in a soluble form. Several approaches have been employed to improve the immunogenicity of HA stem, including conjugation of HA stem with a highly immunogenic carrier protein or displaying HA stem on a nanoparticle scaffold. Converting a weakly immunologic protein into a multimer through aggregation can significantly enhance its immunogenicity, with some multimeric protein aggregates previously shown to be more immunogenic than their soluble counterparts in animal models. Here, we show that a chemically coupling a peptide derived from the head domain of PR8 HA (P35) with the poorly immunogenic HA stem protein results in aggregation of the HA stem which significantly increases stem-specific B cell responses following vaccination. Importantly, vaccination with this conjugate in the absence of adjuvant still induced robust B cell responses against stem in vivo. Improving HA stem immunogenicity by aggregation provides an alternative avenue to conjugation with exotic carrier proteins or nanoparticle formulation.
Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort ...with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.
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•Breakthrough infection elicits a rapid recall of CD4+ and CD8+ spike-specific T cells•CD4+ T cell recall is robust and coordinated, peaking by day 5 post symptoms•CD8+ T cells become activated but variably expand following infection•Spike-specific CD8+ T cell activation inversely correlates with the rate of viral decay
Our understanding of T cell responses to SARS-CoV-2 vaccination and breakthrough infection has lagged behind B cells and antibodies. Here, Koutsakos et al. utilize longitudinal sampling to demonstrate a rapid activation of SARS-CoV-2-specific CD4+ and CD8+ T cells during breakthrough infection. Furthermore, spike-specific CD8+ T cell activation correlates with viral clearance.
Seasonally recurrent influenza virus infections are a significant cause of global morbidity and mortality. In murine models, primary influenza infection in the respiratory tract elicits potent ...humoral responses concentrated in the draining mediastinal lymph node and the spleen. In addition to immunity within secondary lymphoid organs (SLO), pulmonary infection is also associated with formation of ectopic inducible bronchus-associated tissues (iBALT) in the lung. These structures display a lymphoid organization, but their function and protective benefits remain unclear. Here we examined the phenotype, transcriptional profile and antigen specificity of B cell populations forming iBALT in influenza infected mice. We show that the cellular composition of iBALT was comparable to SLO, containing populations of follicular dendritic cells (FDC), T-follicular helper (Tfh) cells, and germinal center (GC)-like B cells with classical dark- and light-zone polarization. Transcriptional profiles of GC B cells in iBALT and SLO were conserved regardless of anatomical localization. The architecture of iBALT was pleiomorphic and less structurally defined than SLO. Nevertheless, we show that GC-like structures within iBALT serve as a distinct niche that independently support the maturation and selection of B cells primarily targeted against the influenza virus nucleoprotein. Our findings suggest that iBALT, which are positioned at the frontline of the lung mucosa, drive long-lived, and unique GC reactions that contribute to the diversity of the humoral response targeting influenza.
Vaccination against SARS-CoV-2 protects from infection and improves clinical outcomes in breakthrough infections, likely reflecting residual vaccine-elicited immunity and recall of immunological ...memory. Here, we define the early kinetics of spike-specific humoral and cellular immunity after vaccination of seropositive individuals and after Delta or Omicron breakthrough infection in vaccinated individuals. Early longitudinal sampling revealed the timing and magnitude of recall, with the phenotypic activation of B cells preceding an increase in neutralizing antibody titers. While vaccination of seropositive individuals resulted in robust recall of humoral and T cell immunity, recall of vaccine-elicited responses was delayed and variable in magnitude during breakthrough infections and depended on the infecting variant of concern. While the delayed kinetics of immune recall provides a potential mechanism for the lack of early control of viral replication, the recall of antibodies coincided with viral clearance and likely underpins the protective effects of vaccination against severe COVID-19.
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•Vaccination of seropositive people elicits robust recall of spike-specific immunity•Immune recall following breakthrough infection is variable in timing and magnitude•Antibody recall during Delta breakthrough infection coincides with viral clearance•Omicron breakthrough infection elicits less extensive immune recall compared with Delta
Koutsakos et al. analyzed the recall of spike-specific immunity following vaccination of seropositive individuals and breakthrough infections in vaccinated individuals. Compared with recall following vaccination, recall during breakthrough infections is delayed and variable in magnitude. The recall of neutralizing antibodies temporally correlated with control of Delta breakthrough infection viral load, while Omicron breakthrough elicited less extensive immune recall versus Delta.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination elicit CD4
T cell responses to the spike protein, including circulating follicular helper T (cT
) cells that ...correlate with neutralizing antibodies. Using a novel HLA-DRB1*15:01/S
tetramer to track spike-specific CD4
T cells, we show that primary infection or vaccination induces robust S
-specific CXCR5
and cT
cell memory responses. Secondary exposure induced recall of CD4
T cells with a transitory CXCR3
phenotype, and drove expansion of cT
cells transiently expressing ICOS, CD38 and PD-1. In both contexts, cells exhibited a restricted T cell antigen receptor repertoire, including a highly public clonotype and considerable clonotypic overlap between CXCR5
and cT
populations. Following a third vaccine dose, the rapid re-expansion of spike-specific CD4
T cells contrasted with the comparatively delayed increase in antibody titers. Overall, we demonstrate that stable pools of cT
and memory CD4
T cells established by infection and/or vaccination are efficiently recalled upon antigen reexposure and may contribute to long-term protection against SARS-CoV-2.
Vδ2+ T cells play a critical role in immunity to micro-organisms and cancer but exhibit substantial heterogeneity in humans. Here, we demonstrate that CD26 and CD94 define transcriptionally, ...phenotypically, and functionally distinct Vδ2+ T cell subsets. Despite distinct antigen specificities, CD26hiCD94lo Vδ2+ cells exhibit substantial similarities to CD26hi mucosal-associated invariant T (MAIT) cells, although CD26− Vδ2+ cells exhibit cytotoxic, effector-like profiles. At birth, the Vδ2+Vγ9+ population is dominated by CD26hiCD94lo cells; during adolescence and adulthood, Vδ2+ cells acquire CD94/NKG2A expression and the relative frequency of the CD26hiCD94lo subset declines. Critically, exposure of the CD26hiCD94lo subset to phosphoantigen in the context of interleukin-23 (IL-23) and CD26 engagement drives the acquisition of a cytotoxic program and concurrent loss of the MAIT cell-like phenotype. The ability to modulate the cytotoxic potential of CD26hiCD94lo Vδ2+ cells, combined with their adenosine-binding capacity, may make them ideal targets for immunotherapeutic expansion and adoptive transfer.
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•Human CD26hiCD94lo Vd2Vg9 T cells exhibit a MAIT cell-like phenotype•CD26 and CD94 regulate Vd2 cytokine responses and cytotoxicity•Cord blood Vd2Vg9 cells are predominately CD26hiCD94lo•Exposure of CD26hiCD94lo cells to antigen and IL-23 induces a cytotoxic phenotype
Wragg et al. identify a population of human gd T cells with striking similarities to MAIT cells. These cells dominate the cord blood Vd2 population and upregulate an effector-like program upon antigen and IL-23 stimulation, providing a potential mechanism by which cytotoxic Vd2 cells may accumulate during adolescence and adulthood.
HIV infection is associated with a rapid and sustained inversion of the Vδ1:Vδ2 T‐cell ratio in peripheral blood. Studies of antiretroviral therapy (ART)‐treated cohorts suggest that ART is ...insufficient to reconstitute either the frequency or function of the γδ T‐cell subset. Recent advances are now beginning to shed light on the relationship between microbial translocation, chronic inflammation, immune ageing and γδ T‐cell immunology. Here, we review the impact of acute, chronic untreated and treated HIV infection on circulating and mucosal γδ T‐cell subsets and highlight novel approaches to harness γδ T cells as components of anti‐HIV immunotherapy.
In this review, we discuss the impact of HIV infection on circulating γδ T‐cell subsets and their antimicrobial function. We highlight current work focusing on the link between chronic inflammation, gut dysbiosis and γδ T‐cell trafficking. Finally, we explore the potential role for γδ T cells as components of anti‐HIV immunotherapy.
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